Next Article in Journal
Two Cysteines in Raf Kinase Inhibitor Protein Make Differential Contributions to Structural Dynamics In Vitro
Next Article in Special Issue
Pyridoxal and Salicylaldehyde Derivatives: Synthesis, Characterization, and Antifungal Potential Against Opportunistic Yeast Pathogens
Previous Article in Journal
The Counteracting Effect of Chrysin on Dietary Fructose-Induced Metabolic-Associated Fatty Liver Disease (MAFLD) in Rats with a Focus on Glucose and Lipid Metabolism
Previous Article in Special Issue
Glycine-Based [3+2] Cycloaddition for the Synthesis of Pyrrolidine-Containing Polycyclic Compounds
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 30
Issue 2
10.3390/molecules30020381
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

5-Aminopyrazole Dimerization: Cu-Promoted Switchable Synthesis of Pyrazole-Fused Pyridazines and Pyrazines via Direct Coupling of C-H/N-H, C-H/C-H, and N-H/N-H Bonds

by
Yi-Xin Chai
1,
Jun-Jie Ren
1,
Yi-Ming Li
1,
Yi-Cheng Bai
1,
Qing-Qing Zhang
1,
Yi-Zhen Zhao
1,
Xue Yang
1,
Xiao-Han Zhang
1,
Xin-Shuang Zhang
1,
An-Xin Wu
3,*,
Yan-Ping Zhu
1,2,* and
Yuan-Yuan Sun
1,*
1
Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, School of Pharmacy, Yantai University, Yantai 264005, China
2
International Innovation Center for Forest Chemicals and Materials, Nanjing Forestry University, Nanjing 210037, China
3
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan 430079, China
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(2), 381; https://doi.org/10.3390/molecules30020381
Submission received: 23 December 2024 / Revised: 12 January 2025 / Accepted: 14 January 2025 / Published: 17 January 2025
(This article belongs to the Special Issue Cyclization Reactions in the Synthesis of Heterocyclic Compounds)
Browse Figures
Versions Notes

Abstract

:
A Cu-promoted highly chemoselective dimerization of 5-aminopyrazoles to produce pyrazole-fused pyridazines and pyrazines is reported. The protocol generates switchable products via the direct coupling of C-H/N-H, C-H/C-H and N-H/N-H bonds, with the merits of broad substrate scope and high functional group compatibility. Gram-scale experiments demonstrated the potential applications of this reaction. Moreover, the preliminary fluorescence results uncovered that dipyrazole-fused pyridazines and pyrazines may have some potential applications in materials chemistry.

1. Introduction

Nitrogen-containing heterocyclic molecules have received a great deal of attention from the synthetic chemistry community due to the large-scale biological activities they possess [1]. Pyridazines and pyrazines, and important subsets thereof, are widely used in synthetic pharmaceuticals, chemicals, dyes, materials, etc., which have an important place in academia and industry. These compounds have been shown to be vasodilators (A1) [2], anticonvulsant (A2) [3], antibiotics (A3) [4], anticancer agents (A4–A5) [5,6], antimicrobial agents (A6) [7], virus inhibitors (A7) [8], and proteasome inhibitors (A8) [9] (Figure 1). Thus, pyridazine and pyrazine scaffolds have become hot research topics and have triggered continuous synthetic innovations.
The construction of C-C, C-N, and N=N bonds has been a hot topic in the research of medicinal chemistry over past decades, in which the direct functionalization of C-H bond applied to dehydrogenation coupling reactions has made great progress [10,11,12,13,14,15]. Among them, Csp2-Csp2 bond is essential for the synthesis of π-conjugated molecules, and Csp2-N bond is prevalent in pharmaceutically active molecules. Various methods exist for constructing Csp2-Csp2 and Csp2-N bonds, with the coupling of functionalized dehydrogenation from Csp2-H being one of the most powerful and reliable approaches. The classical method is transition metal catalysis, such as palladium, iridium, copper, silver, manganese, etc. (Scheme 1a) [16,17,18,19,20,21,22,23]. Metal-free synthetic approaches to construct Csp2-Csp2 bond and Csp2-N bond that utilize inorganic catalysts, such as I2, I (III), K2S2O8, NIS, etc., have also been reported via the dehydrogenation coupling reaction (Scheme 1b) [24,25,26,27]. For instance, Liang and co-workers developed a facile iodine-promoted regioselective C-H/C-H and C-H/N-H coupling of indoles with indoles or amines to give 2,3′-biindoles and 4-(1H-indol-2-yl)morpholines [28]. As the concept of green synthesis is becoming more and more popular, photocatalysis and electrochemistry-induced Csp2-H functionalized dehydrogenation coupling were developed (Scheme 1c) [29,30,31,32,33]. For instance, Li and co-workers developed a cobalt-promoted electrochemical 1,2-diarylation of alkenes with electron-rich aromatic hydrocarbons via direct dual C-H functionalization to generate polyaryl-functionalized alkanes [34]. Lei’s group has successively reported the synthesis of imidazopyridines, triarylamine derivatives, and polycyclic indoline derivatives via electro-oxidation dehydrogenation [35,36,37].
Hydrazine derivatives have diverse applications in fields such as pharmaceuticals and dyes. In recent years, compared to conventional metal catalysts (Scheme 1d) [38,39], the electrochemical dehydrogenation of N-H/N-H coupling has become a powerful tool for the construction of N-N bond (Scheme 1e) [40,41]. For example, Chen’s group reported an electrochemically induced N-H/N-H dehydrogenation strategy of N-phenylpyridin-2-amine to construct N-N bond for the synthesis of hydrazine analogs [42]. Additionally, the self-coupling of brominated arylheterocycles to build bis-arylheterocyclic fragments has also received much attention in this field. For example, Tang’s group developed an effective Pd-catalyzed homocoupling of heteroaryl bromides for the formation of a series of symmetrical biheteroaryls, featuring a tandem Miyaura borylation, known as the Suzuki coupling sequence (Scheme 1f) [43].
Despite the abovementioned good achievements, approaches for synthesizing pyrazole-fused pyridazines or pyrazines are rarely reported. Recently, Baruah’s group developed a Cu(I)-catalyzed annulation of aminopyrazoles to synthesize pyridazine in the presence of Ag2CO3 and benzoic acid; furthermore, in the absence of benzoic acid, intermediate E-diazo compounds are generated [44]. However, the method for synthesizing pyrazole-fused pyrazines has not yet been reported. As shown in Scheme 1g, herein we describe the example of the Cu-catalyzed highly chemoselective dimerization of 5-aminopyrazoles to produce dipyrazole-fused pyridazines and pyrazines. The protocol generates switchable products via the direct coupling of C-H/N-H, C-H/C-H, and N-H/N-H bonds.

2. Results and Discussion

3-Methyl-1-phenyl-1H-pyrazol-5-amine 1a was selected as the model substrate for the screening and optimization of the reaction conditions. Under the initial conditions shown in entry 1 of Table S1 for 1a (0.2 mmol) using Cu(OAc)2 as a catalyst, the desired product 2a was obtained with a yield of 50%. Subsequently, we investigated the effect of the type of oxidants on the reaction; it was found that when benzoyl peroxide was used as an oxidant, a yield of 58% was achieved (Table 1, entries 2–5). Then, the different catalyst types were studied, and it was found that the yields were all reduced (Table 1, entries 6–12). The effect of temperature on the method was also tested. These results showed that the optimal reaction temperature was 100 °C (Table 1, entries 13–16). When continuing the study of the equivalent of Cu(OAc)2, it was found that the yield was decreased when the amount of Cu(OAc)2 was decreased (Table 1, entries 17–18). Benzoyl peroxide equivalents were also tested, and the best yield was found at 0.5 equivalent (Table 1, entries 19–20). The solvents were also investigated; the yields did not improve well (Table 1, entries 21–25). Finally, the effect of adding three different additives was tested, and it was found that the addition of K2S2O8 resulted in a significant increase in yield (Table 1, entries 26–28). Following this, the equivalent of K2S2O8 was investigated and it was found that the highest yield was achieved when the equivalent of K2S2O8 was 2.5 (Table 1, entries 29–30). Finally, we found the following optimal conditions to synthesize 2a [45]: 3-methyl-1-phenyl-1H-pyrazol-5-amine (1a) (0.2 mmol), Cu(OAc)2 (3.0 equiv.), benzoyl peroxide (BPO) (0.5 equiv.), and K2S2O8 (2.5 equiv.), and these were heated in toluene (2 mL) at 100 °C for 10 h under air.
After the optimal reaction conditions were determined, the substrate scope of 5-aminopyrazoles was explored to synthesize dipyrazole-fused pyridazines (Figure 2). Firstly, when R1 is the methyl group, the reactions of different substituents on R2 were tested. To our delight, the protocol showed excellent tolerance to substituted phenyls containing electron-donating and electron-absorbing groups. All substrates proceeded smoothly to afford the desired products in moderate to good yields (2a–2i, 58–79%); when R2 is the methyl group, the yield of product 2j is 50%. Moreover, when R2 is naphthalene, the target product can be obtained with a good yield (2k, 70%). When R2 is phenyl and R1 is ethyl, phenyl, thienyl, and 4-F-phenyl, respectively, all reactions gave the target products in moderate to good yields (2l–2o, 58–78%). Finally, when R1 is the 4-F-phenyl group and R2 is the 4-methylphenyl group, 2p can still be obtained in 60% yield. It should be mentioned that when either R1 or R2 is the tert-butyl group, perhaps because of the site resistance, dipyrazole-fused pyridazines 2q, 2r, and 2s were not formed; only new isomer dipyrazole-fused pyrazines were obtained in moderate yields (3q–3s, 58–62%). Moreover, the compound 3q [45] was further confirmed by X-ray crystallographic analysis. In addition, 4-amino-2H-chromen-2-one and ethyl (E)-3-amino-3-phenylacrylate are not applicable to this reaction, and no target compounds are formed.
Due to the emergence of new configurations, this has sparked a great deal of interest and prompted us to subject 3a to condition optimization. 3-Methyl-1-phenyl-1H-pyrazol-5-amine 1a was still chosen as the substrate model. Under the initial conditions shown in entry 1 of Table 2 for 1a (0.2 mmol) using Cu(OAc)2 as a catalyst, the desired product 3a was obtained with a yield of 36%. Different oxidants were then tested, and the addition of tert-butyl peroxybenzo resulted in an increase in yield (Table 2, entries 2–5). Subsequently, different Cu catalysts were experimented on, and it was found that the yield was enhanced when CuCl2 was used as the catalyst (Table 2, entries 6–10). Then, the addition of different additives was used to test the experimental effect, and it was found that the addition of Na2CO3 promotes the reaction and results in an increase in yield (Table 2, entries 11–15). Different solvents were also screened, but all resulted in lower yields (Table 2, entries 16–22). Subsequently, it was found that the addition of 1,10-phenantnroline leads to a higher increase in yield (Table 2, entries 23–24). Based on this, we changed the temperature to observe the experimental effect and found that the optimal reaction temperature was still 130 °C (Table 2, entries 25–27). Finally, the yield decreased when the equivalent of CuCl2 was increased to 40% or decreased to 10% (Table 2, entries 28–29). We screened the conditions to obtain the best solution to synthesize 3a [45]: 1a (0.2 mmol), CuCl2 (20 mol%), 1,10-phenanthroline (0.3 equiv.), tert-butyl peroxybenzoate (0.5 equiv.), and Na2CO3 (2.5 equiv.) were heated in toluene (2 mL) at 130 °C for 12 h under air.
Next, due to the emergence of new configurations, we tested different species of 5-aminopyrazoles to synthesize dipyrazole-fused pyrazines (Figure 3). When R1 is a methyl group, different substituted substrates (e.g., 2-Me, 4-Me, 4-iPr, 3,4-(Me)2, 3,5-(Me)2, 3-Cl, 4-CF3, 2,4-Cl2) on phenyl rings 1b–1i could participate in this reaction, giving the desired products 3b–3i in 40–59% yields. To our delight, compared to phenyl-substituted 5-aminopyrazoles, methyl- and naphthalene-substituted substrates also worked well, giving the corresponding products in moderate yields (3j–3k, 57–60%). When R2 is phenyl, whether R1 is alkyl or aryl (e.g., -nPr, -Ph), these substrates performed the reactions smoothly to give the desired products in medium yields (3l–3m, 58–60%). Meanwhile, in this transformation process, whether R1 or R2 is tert-butyl can also be tolerated, leading to the final products being in moderate yields (3q–3s, 40–45%). In the same way, under the conditions shown in Figure 3, both 4-amino-2H-chromen-2-one and ethyl (E)-3-amino-3-phenylacrylate cannot produce the desired target products.
To establish the mechanism, several control experiments were conducted. The addition of the radical scavenger TEMPO or BHT (5.0 equiv.) under the standard conditions of Scheme 2 or 3, respectively, was found to completely inhibit the formation of 2a or 3a. The crude reaction solution was subjected to HRMS, with the product of 1a binding to TEMPO or BHT, which could be found under the two conditions, respectively (Scheme 2a and 2b). This demonstrated that this reaction was performed involving the radical pathway. Then, 1a was reacted with (1-cyclopropylvinyl) benzene 5 (5.0 equiv.) under Scheme 2 or Scheme 3 standard conditions, and the results showed that the yields of both 2a and 3a were decreased, and the adduct could be detected in the crude reaction solution through HRMS (Scheme 2c). Moreover, the production of potential intermediates was, respectively, detected by HRMS after 2 h of the Scheme 2 or Scheme 3 reactions (Scheme 2d). We assessed whether the azo compound (E)-1,2-bis(3-methyl-1-phenyl-1H-pyrazol-5-yl) diazene 4a could produce 2a or 3a under Scheme 2 or Scheme 3 standard conditions; the results showed that 2a or 3a was not produced, suggesting that 4a is not a reaction intermediate (Scheme 2e). We then tested the reaction with Scheme 2 or Scheme 3 standard conditions under argon atmosphere and found that the yield was only 8% for 2a and 6% for 3a, thus demonstrating that oxygen is necessary for the reaction to proceed (Scheme 2f). As shown in Scheme 2g, when the amount of substrate 1a was scaled-up to 1.0 mmol, the products 2a and 3a could still be obtained in 60% and 48% yields, respectively.
Based on our observations and literature reports [46,47,48], a plausible reaction mechanism is depicted (Scheme 3). 5-Aminopyrazole (1a) reacted with Cu(II) to give intermediate A through a SET pathway. After the deprotonation, N radical B1 or C radical B2 may form. In path a, B1 and B2 underwent C-N radical coupling to generate intermediate C1, which could undergo structural mutual transformation to obtain D1. D1 underwent Cu-mediated one-electron oxidation and deprotonation to obtain N radical E1. Subsequently, F1 was obtained by radical addition. 3a could finally be achieved through successive Cu-mediated SET, deprotonation, and oxidative dehydrogenation from intermediate F1. In path b, B2 and B2 underwent C-C radical coupling to generate intermediate C2, which could undergo structural mutual transformation to obtain D2. Amino cationic radical E2 was obtained through Cu-mediated SET. E2 lost two protons to obtain N radical F2. From F2, N-N radical coupling and oxidative dehydrogenation successively occurred to form 2a.
Most of the synthetic compounds showed a fluorescent nature during UV monitoring (see Supplementary Materials Figure S4). We proceeded to characterize their fluorescence performance (Figure 4 and Figure 5). The UV absorption wavelengths of compound 2 ranged from 266 to 309 nm. The fluorescence emission of them ranged from 293 to 511 nm (Table 3). In compound 2, when R1 is a methyl group and R2 is a benzene ring, the quantum yield of most products with different substituents on the benzene ring (2b–2d, 2f–2i) is higher than that of unsubstituted products (2a). The quantum yields of the bis-methyl-substituted product (2j) were slightly higher than those of the bis-phenyl-substituted product (2m). The UV absorption wavelengths of compound 3 ranged from 274 to 304 nm. The fluorescence emission of them ranged from 474 to 544 nm (Table 4). Interestingly, the above fluorescence quantum yield trend observed in compound 3 is opposite to that of compound 2. Finally, we tested the effect of solvent polarity on the fluorescence spectra and found that compounds 2 and 3 both showed significant red and blue shifts in DCM and toluene, while the emission maxima in ACN, DMSO, and CH3OH were almost the same (Figure 6).

3. Materials and Methods

3.1. General Information

Analytical thin-layer chromatography (TLC) was performed by using pre-coated silica gel HF254 glass plates. Column chromatography was performed by using silica gel (200–300 mesh). The 1H NMR and 13C NMR spectra were recorded on a Bruker Advance 500 or 400 MHz instrument at 500 or 400 MHz (1H NMR) and 126 or 101 MHz (13C NMR). We used the residual solvent peak in CDCl3 as an internal reference (δ = 7.26 for 1H and δ = 77.0 for 13C{1H}). Chemical shifts (δ) are reported in ppm relative to the internal standard of tetramethylsilane (TMS). The coupling constants (J) are quoted in Hz (hertz). Resonances are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), or combinations thereof. High-resolution mass spectra (HRMS) were obtained on Thermo Scientific Q-Exactive (ESI mode, Q-Exactive Orbitrap MS system) (From Thermo Fisher Scientific, Shanghai, China). The melting points were measured with the SGW X-4 apparatus (From INESA, Shanghai, China). Data collection for the crystal structure was performed by using Mo Kα radiation on a Bruker Smart APEX CCD area-detector diffractometer (From Bruker, Beijing, China). UV data were recorded by Shimadzu UV 2000 (From Shimadzu, Jiangsu, China) at ambient temperature, and fluorescence data were recorded by HITACHI F7000 (From HITACHI, Beijing, China) at ambient temperature.

3.2. Synthetic Procedures

What follows is the general procedure for the synthesis of 2 (2a as an example). 3-Methyl-1-phenyl-1H-pyrazol-5-amine (1a) (35 mg, 0.2 mmol, 1.0 equiv.), Cu(OAc)2 (55 mg, 0.3 mmol, 3.0 equiv.), benzoyl peroxide (BPO) (12 mg, 0.05 mmol, 0.5 equiv.), and K2S2O8 (68 mg, 0.25 mmol, 2.5 equiv.) were added to a screw-cap test tube, and then the solvent of toluene (2.0 mL) was added. The mixture was then stirred at 100 °C in an oil bath for 10 h under air atmosphere. After the reaction was completed (monitored by TLC), 50 mL of water was added to the mixture, which was then extracted three times with CH2Cl2 (3 × 50 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residues were purified by column chromatography (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1) to obtain the corresponding products 2a (27 mg, 79%) (Scheme 4).
General procedure for the synthesis of 3 (3a as an example). 3-Methyl-1-phenyl-1H-pyrazol-5-amine (1a) (35 mg, 0.2 mmol, 1.0 equiv.), CuCl2 (3.0 mg, 0.02 mmol, 20 mol%), 1,10-phenanthroline (5.4 mg, 0.03 mmol, 0.3 equiv.), tert-butyl peroxybenzoate (10 uL, 0.05 mmol, 0.5 equiv.), and Na2CO3 (27 mg, 0.25 mmol, 2.5 equiv.) were added to a screw-cap test tube, and then the solvent of toluene (2.0 mL) was added. The mixture was then stirred at 130 °C in an oil bath for 12 h under air atmosphere. After the reaction was completed (monitored by TLC), 50 mL of water was added to the mixture, which was then extracted three times with CH2Cl2 (3 × 50 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residues were purified by column chromatography (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1) to obtain the corresponding products 3a (20mg, 59%) (Scheme 5).

3.3. Characterization of Products

  • 1,8-Dimethyl-3,6-diphenyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e]pyridazine (2a), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 27 mg, 70%, yellow solid, m.p.: 242–243 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.46–8.41 (m, 4H), 7.60–7.55 (m, 4H), 7.40–7.35 (m, 2H), 3.01 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 150.6, 140.3, 139.2, 129.2, 126.6, 121.6, 109.7, 15.4. HRMS (ESI): m/z [M + H]+ calcd. for C20H17N6: 341.1509; found: 341.1505.
  • 1,8-Dimethyl-3,6-di-o-tolyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e]pyridazine (2b), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 22 mg, 60%, yellow solid, m.p.: 220–221 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.50 (d, J = 7.2 Hz, 2H), 7.43–7.40 (m, 4H), 7.39–7.34 (m, 2H), 3.01 (s, 6H), 2.21 (s, 6H). 13C NMR (101 MHz, CDCl3) δ (ppm) 151.3, 140.1, 137.2, 135.5, 131.3, 129.2, 127.9, 126.6, 108.1, 18.4, 15.3. HRMS (ESI): m/z [M + H]+ calcd. for C22H21N6: 369.1822; found: 369.1812.
  • 1,8-Dimethyl-3,6-di-p-tolyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e]pyridazine (2c), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 21 mg, 58%, yellow solid, m.p.: 272–273 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.27 (d, J = 8.5 Hz, 4H), 7.36 (d, J = 8.5 Hz, 4H), 2.98 (s, 6H), 2.44 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 150.4, 139.9, 136.8, 136.4, 129.8, 121.5, 109.4, 21.1, 15.4. HRMS (ESI): m/z [M + Na]+ calcd. for C22H21N6: 369.1822; found: 369.1816.
  • 3,6-Bis(4-isopropylphenyl)-1,8-dimethyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2d), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 26 mg, 61%, yellow solid, m.p.: 227–228 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.29 (d, J = 8.5 Hz, 4H), 7.42 (d, J = 8.5 Hz, 4H), 3.05–3.00 (m, 2H), 2.99 (s, 6H), 1.33 (s, 6H), 1.31 (s, 6H). 13C NMR (101 MHz, CDCl3) δ (ppm) 150.5, 147.5, 140.0, 137.0, 127.2, 121.7, 109.4, 33.8, 24.0, 15.4. HRMS (ESI): m/z [M + H]+ calcd. for C26H29N6: 425.2448; found: 425.2440.
  • 3,6-Bis(3,4-dimethylphenyl)-1,8-dimethyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2e), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 23 mg, 59%, yellow solid, m.p.: 269–270 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.10 (d, J = 6.4 Hz, 4H), 7.31 (d, J = 8.8 Hz, 2H), 2.98 (s, 6H), 2.40 (s, 6H), 2.35 (s, 6H). 13C NMR (101 MHz, CDCl3) δ (ppm) 150.5, 139.8, 137.6, 137.0, 135.2, 130.2, 122.8, 119.3, 109.3, 20.1, 19.4, 15.4. HRMS (ESI): m/z [M + H]+ calcd. for C24H25N6: 397.2135; found: 397.2125.
  • 3,6-Bis(3,5-dimethylphenyl)-1,8-dimethyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2f), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 25 mg, 63%, yellow solid, m.p.: 272–273 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.99 (s, 4H), 7.02 (s, 2H), 2.99 (s, 6H), 2.46 (s, 12H). 13C NMR (101 MHz, CDCl3) δ (ppm) 150.5, 140.0, 139.0, 128.5, 119.6, 109.4, 29.7, 21.5, 15.4. HRMS (ESI): m/z [M + H]+ calcd. for C24H25N6: 397.2135; found: 397.2134.
  • 3,6-Bis(3-chlorophenyl)-1,8-dimethyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2g), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 29 mg, 70%, yellow solid, m.p.: 251–252 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.50–8.44 (m, 4H), 7.50 (t, J = 8.0 Hz, 2H), 7.34 (ddd, J = 8.1, 2.0, 1.0 Hz, 2H), 2.99 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 150.7, 141.0, 140.1, 135.1, 130.3, 126.6, 121.3, 119.2, 110.1, 15.4. HRMS (ESI): m/z [M + H]+ calcd. for C20H15Cl2N6: 409.0730; found: 409.0723.
  • 1,8-Dimethyl-3,6-bis(4-(trifluoromethyl)phenyl)-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2h), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 28 mg, 58%, white solid, m.p.: 252–253 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.70 (d, J = 8.5 Hz, 4H), 7.83 (d, J = 8.5 Hz, 4H), 3.01 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 150.9, 141.8, 141.5, 126.5 (q, JCF = 3.7 Hz), 120.8, 110.5, 15.5. 19F NMR (470 MHz, CDCl3) δ (ppm) −62.13. HRMS (ESI): m/z [M + H]+ calcd. for C22H15F6N6: 477.1257; found: 477.1249.
  • 3,6-Bis(2,4-dichlorophenyl)-1,8-dimethyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2i), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 33 mg, 70%, yellow solid, m.p.: 199–200 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (d, J = 2.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.45 (dd, J = 8.5, 2.0 Hz, 2H), 3.01 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 151.4, 141.5, 135.8, 134.4, 133.0, 130.6, 130.5, 127.9, 108.8, 15.4. HRMS (ESI): m/z [M + H]+ calcd. for C20H13Cl4N6: 476.9950; found: 476.9943.
  • 1,3,6,8-Tetramethyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2j), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 11 mg, 50%, yellow solid, m.p.: 106–107 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.39 (s, 6H), 2.84 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 150.6, 138.0, 107.4, 35.1, 14.9. HRMS (ESI): m/z [M + H]+ calcd. for C10H13N6: 217.1196; found: 217.1188.
  • 1,8-Dimethyl-3,6-di(naphthalen-2-yl)-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2k), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 30 mg, 68%, yellow solid, m.p.: 242–243 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.96 (d, J = 2.4 Hz, 2H), 8.59 (dd, J = 9.2, 2.4 Hz, 2H), 8.05–7.99 (m, 4H), 7.90 (d, J = 8.0 Hz, 2H), 7.57–7.49 (m, 4H), 3.01 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 150.8, 140.5, 136.8, 133.6, 131.9, 129.2, 128.4, 127.7, 126.7, 126.0, 120.4, 119.0, 109.8, 15.5. HRMS (ESI): m/z [M + H]+ calcd. for C28H21N6: 441.1822; found: 441.1815.
  • 1,8-Diethyl-3,6-diphenyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2l), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 29 mg, 78%, yellow solid, m.p.: 246–247 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.45 (d, J = 7.5 Hz, 4H), 7.57 (t, J = 7.5 Hz, 4H), 7.37 (t, J = 7.5 Hz, 2H), 3.37 (q, J = 7.5 Hz, 4H), 1.58 (d, J = 7.5 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 150.5, 145.6, 139.3, 129.2, 126.5, 121.6, 108.9, 22.8, 13.4. HRMS (ESI): m/z [M + H]+ calcd. for C22H21N6: 369.1822; found: 369.1817.
  • 1,3,6,8-Tetraphenyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2m), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 35 mg, 76%, orange solid, m.p.: 217–218 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.54–8.50 (m, 4H), 7.64–7.59 (m, 4H), 7.43 (t, J = 7.6 Hz, 2H), 7.37 (d, J = 6.8 Hz, 4H), 7.21 (t, J = 7.6 Hz, 2H), 7.03 (t, J = 8.0 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ (ppm) 151.1, 144.7, 139.1, 132.3, 129.3, 128.6, 127.8, 127.2, 122.3, 108.2. HRMS (ESI): m/z [M + H]+ calcd. for C30H21N6: 465.1822; found: 465.1813.
  • 3,6-Diphenyl-1,8-di(thiophen-2-yl)-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2n), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 28 mg, 58%, orange solid, m.p.: 253–354 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.46 (d, J = 8.0 Hz, 4H), 7.61 (t, J = 8.0 Hz, 4H), 7.44 (t, J = 7.5 Hz, 2H), 7.32 (d, J = 5.0 Hz, 2H), 6.82 (d, J = 3.5 Hz, 2H), 6.80–6.78 (m, 2H). 13C NMR (126 MHz, CDCl3) δ (ppm) 150.8, 138.8, 138.6, 133.0, 129.3, 129.0, 127.5, 127.4, 126.8, 122.5, 108.4. HRMS (ESI): m/z [M + H]+ calcd. for C26H17N6S2: 477.0951; found: 477.0945.
  • 1,8-Bis(4-fluorophenyl)-3,6-diphenyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2o), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 32 mg, 64%, orange solid, m.p.: 254–255 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.51–8.47 (m, 4H), 7.64–7.59 (m, 4H), 7.47–7.42 (m, 2H), 7.37–7.32 (m, 4H), 6.84–6.77 (m, 4H). 13C NMR (126 MHz, CDCl3) δ (ppm) 164.6, 162.1, 151.0, 143.5, 139.0, 130.4 (d, JCF = 8.3 Hz), 128.4, 127.4, 122.3, 115.0, 114.9 (d, JCF = 21.9 Hz), 108.0. 19F NMR (470 MHz, CDCl3) δ (ppm) −112.51. HRMS (ESI): m/z [M + H]+ calcd. for C30H19F2N6: 501.1634; found: 501.1626.
  • 1,8-Bis(4-fluorophenyl)-3,6-di-p-tolyl-3,6-dihydrodipyrazolo [3,4-c:4′,3′-e] pyridazine (2p), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 5:1), 32 mg, 60%, orange solid, m.p.: 253–254 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.33 (d, J = 8.5 Hz, 4H), 7.40 (d, J = 8.5 Hz, 4H), 7.33 (dd, J = 8.5, 5.5 Hz, 4H), 6.79 (t, J = 8.5 Hz, 4H), 2.47 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 164.3, 162.3, 150.8, 143.1, 137.3, 136.6, 130.4 (d, JCF = 8.3 Hz), 128.5 (d, JCF = 3.2 Hz), 122.2, 115.0, 114.8 (d, JCF = 22.0 Hz), 107.8, 21.1. 19F NMR (470 MHz, CDCl3) δ (ppm) −112.67. HRMS (ESI): m/z [M + H]+ calcd. for C32H23F2N6: 529.1947; found: 529.1939.
  • 3,7-Dimethyl-1,5-diphenyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3a), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 20 mg,59%, orange solid, m.p.: 276–277 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.40 (d, J = 8.0 Hz, 4H), 7.57 (t, J = 8.0 Hz, 4H), 7.32 (t, J = 7.5 Hz, 2H), 2.84 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 143.1, 142.3, 139.5, 134.1, 129.2, 125.6, 119.8, 11.6. HRMS (ESI): m/z [M + H]+ calcd. for C20H17N6: 341.1509; found: 341.1501.
  • 3,7-Dimethyl-1,5-di-o-tolyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3b), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 19 mg, 52%, yellow solid, m.p.: 234–235 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.50–7.47 (m, 2H), 7.44 (td, J = 7.1, 6.6, 2.1 Hz, 4H), 7.41–7.36 (m, 2H), 2.74 (s, 6H), 2.28 (s, 6H). 13C NMR (101 MHz, CDCl3) δ (ppm) 143.3, 142.6, 137.3, 135.5, 133.3, 131.4, 128.7, 127.7, 126.7, 18.7, 11.7. HRMS (ESI): m/z [M + H]+ calcd. for C22H21N6: 369.1822; found: 369.1816.
  • 3,7-Dimethyl-1,5-di-p-tolyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3c), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 17 mg, 46%, yellow solid, m.p.: 273–274 °C. Due to the low solubility of the product, 0.6 mL of CDCl3/TFA (v:v = 20:1) was used to measure the NMR spectrum. 1H NMR ((400 MHz, CDCl3/TFA = 20:1(v:v)) δ (ppm) 7.71 (d, J = 8.4 Hz, 4H), 7.43 (d, J = 8.0 Hz, 4H), 2.87 (s, 6H), 2.48 (s, 6H). 13C NMR (101 MHz, CDCl3/TFA = 20:1(v:v)) δ (ppm) 162.3 (q, JCF = 43.8 Hz, CO), 143.40, 142.11, 139.87, 133.84, 133.62, 130.53, 124.03, 114.3 (q, JCF = 285.6 Hz, CF3), 20.95, 10.76. HRMS (ESI): m/z [M + H]+ calcd. for C17H14NO5: 369.1822; found: 369.1813.
  • 1,5-Bis(4-isopropylphenyl)-3,7-dimethyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3d), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 19 mg, 45%, white solid, m.p.: 236–237 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.26 (d, J = 8.6 Hz, 4H), 7.42 (d, J = 8.6 Hz, 4H), 3.00 (m, 2H), 2.82 (s, 6H), 1.33 (d, J = 6.9 Hz, 12H). 13C NMR (101 MHz, CDCl3) δ 146.3, 142.6, 142.1, 137.3, 133.9, 127.2, 120.0, 33.8, 24.1, 11.6. HRMS (ESI): m/z [M + H]+ calcd. for C26H29N6: 425.2448; found: 425.2441.
  • 1,5-Bis(3,4-dimethylphenyl)-3,7-dimethyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3e), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 23 mg, 59%, yellow solid, m.p.: 251–252 °C. Due to the low solubility of the product, 0.6 mL of CDCl3/TFA (v:v = 20:1) was used to measure the NMR spectrum. 1H NMR (500 MHz, CDCl3/TFA = 20:1(v:v)) δ (ppm) 7.55 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 2.87 (s, 1H), 2.38 (s, 3H). 13C NMR (126 MHz, CDCl3/TFA = 20:1(v:v)) δ (ppm) 162.2 (q, JCF = 44.1 Hz, CO), 143.1, 142.0, 138.8, 138.5, 133.7, 130.9, 125.1, 121.5, 114.3 (q, JCF = 285.4 Hz, CF3), 19.7, 19.4, 10.8. HRMS (ESI): m/z [M + H]+ calcd. for C24H25N6: 397.2135; found: 397.2125.
  • 1,5-Bis(3,5-dimethylphenyl)-3,7-dimethyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3f), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 21 mg, 52%, yellow solid, m.p.: 254–255 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.98 (s, 4H), 6.97 (s, 2H), 2.83 (s, 6H), 2.47 (s, 12H). 13C NMR (101 MHz, CDCl3) δ (ppm) 153.3, 142.7, 142.2, 139.3, 139.0, 134.0, 127.4, 117.9, 21.6, 11.6. HRMS (ESI): m/z [M + H]+ calcd. for C24H25N6: 397.2135; found: 397.2123.
  • Methyl 6-chloro-9-oxo-3,3a-dihydro-9H-chromeno [3,2-c]isoxazole-3-carboxylate (3g), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 16 mg, 40%, yellow solid, m.p.: 238–239 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.47 (s, 2H), 8.39 (d, J = 8.5 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.28 (d, J = 10.0 Hz, 2H), 2.84 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 143.8, 142.3, 140.4, 135.0, 134.2, 130.3, 125.5, 119.5, 117.3, 11.6. HRMS (ESI): m/z [M + H]+ calcd. for C20H15Cl2N6: 397.2135; found: 397.2130.
  • 3,7-Dimethyl-1,5-bis(4-(trifluoromethyl)phenyl)-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3h), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 26 mg, 54%, yellow solid, m.p.: 252–253 °C. Due to the low solubility of the product, 0.6 mL of CDCl3/TFA (v:v = 20:1) was used to measure the NMR spectrum. 1H NMR (500 MHz, CDCl3/TFA = 20:1 (v:v)) δ (ppm) 8.34 (d, J = 8.0 Hz, 4H), 7.88 (d, J = 8.5 Hz, 4H), 2.90 (s, 6H). 13C NMR (126 MHz, CDCl3/TFA = 20:1 (v:v)) δ (ppm) 162.2 (q, JCF = 44.0 Hz, CO), 145.1, 142.6, 140.6, 134.5, 126.9 (q, JCF = 3.7 Hz), 121.2, 114.2(q, JCF = 284.8 Hz, CF3), 11.2. 19F NMR (470 MHz, CDCl3) δ (ppm)-62.13. HRMS (ESI): m/z [M + H]+ calcd. for C22H15F6N6: 477.1257; found: 477.1249.
  • 1,5-Bis(2,4-dichlorophenyl)-3,7-dimethyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3i), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 22 mg, 46%, light yellow solid, m.p.: 256–257 °C. Due to the low solubility of the product, 0.6 mL of CDCl3/TFA (v:v = 20:1) was used to measure the NMR spectrum. 1H NMR (500 MHz, CDCl3/TFA = 20:1 (v:v)) δ (ppm) 7.69 (d, J = 2.5 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.51 (dd, J = 8.5, 2.5 Hz, 2H), 2.80 (s, 6H). 13C NMR (126 MHz, CDCl3/TFA = 20:1 (v:v)) δ (ppm) 161.7 (q, JCF = 43.5Hz, CO), 144.5, 143.1, 137.4, 133.8, 133.4, 132.3, 130.8, 130.8, 128.4, 114.2 (q, JCF = 284.8Hz, CF3). HRMS (ESI): m/z [M + H]+ calcd. for C20H13Cl4N6: 476.9950; found: 476.9945.
  • 1,3,5,7-Tetramethyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3j), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 12 mg, 57%, yellow solid, m.p.: 216–217 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 4.16 (s, 6H), 2.72 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 142.9, 140.1, 132.6, 34.1, 11.5. HRMS (ESI): m/z [M + H]+ calcd. for C10H13N6: 217.1196; found: 217.1190.
  • 3,7-Dimethyl-1,5-di(naphthalen-2-yl)-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3k), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 26 mg, 60%, yellow solid, m.p.: 252–253 °C. Due to the low solubility of the product, 0.6 mL of CDCl3/TFA (v:v = 20:1) was used to measure the NMR spectrum. 1H NMR (500 MHz, CDCl3/TFA = 20:1 (v:v)) δ 8.45 (s, 2H), 8.10 (d, J = 1.5 Hz, 4H), 7.97 (ddd, J = 12.0, 7.6, 2.0 Hz, 4H), 7.61 (m, 4H), 2.93 (s, 6H). 13C NMR (126 MHz, CDCl3/TFA = 20:1 (v:v)) δ 162.1 (q, JCF = 42.8 Hz, CO), 144.01, 142.41, 134.29, 134.13, 133.45, 132.68, 129.99, 128.27, 128.01, 127.45, 127.09, 121.35, 120.98, 114.2 (q, JCF = 284.8 Hz, CF3), 11.01. HRMS (ESI): m/z [M + H]+ calcd. for C28H21N6: 441.1822; found: 441.1816.
  • 1,5-Diphenyl-3,7-dipropyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3l), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 24 mg, 60%, yellow solid, m.p.: 228–229 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.42 (d, J = 7.4 Hz, 4H), 7.59–7.55 (m, 4H), 7.31 (t, J = 7.5 Hz, 2H), 3.23 (t, J = 7.5 Hz, 4H), 2.07 (m, 4H), 1.12 (t, J = 7.5 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 146.8, 142.3, 139.6, 133.8, 129.2, 125.4, 119.7, 28.5, 21.6, 14.1. HRMS (ESI): m/z [M + H]+ calcd. for C24H25N6: 397.2135; found: 397.2127.
  • 1,3,5,7-Tetraphenyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3m), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 27 mg, 58%, orange solid, m.p.: 275–276 °C. Due to the low solubility of the product, 0.6 mL of CDCl3/TFA (v:v = 20:1) was used to measure the NMR spectrum. 1H NMR (400 MHz, CDCl3/TFA = 20:1 (v:v)) δ (ppm) 8.45 (d, J = 6.4 Hz, 4H), 8.17 (d, J = 7.6 Hz, 4H), 7.71–7.51 (m, 12H). 13C NMR (101 MHz, CDCl3/TFA = 20:1 (v:v)) δ (ppm) 162.7 (q, JCF = 43.4 Hz, CO), 158.1, 137.3, 130.8, 129.9, 129.5, 128.6, 128.1, 123.2, 114.4 (q, JCF = 285.8 Hz, CF3). HRMS (ESI): m/z [M + H]+ calcd. for C30H21N6: 465.1822; found: 465.1816.
  • 1,5-Di-tert-butyl-3,7-dimethyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3q), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 12 mg, 40%, yellow solid, m.p.: 228–229 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 2.68 (s, 6H), 1.85 (s, 18H). 13C NMR (101 MHz, CDCl3) δ (ppm) 142.3, 138.8, 132.7, 59.9, 29.1, 11.3. HRMS (ESI): m/z [M + H]+ calcd. for C16H25N6: 301.2135; found: 301.2134.
  • 3,7-Di-tert-butyl-1,5-diphenyl-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3r), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 19 mg, 45%,yellow solid, m.p.: 252–253 °C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.49–8.44 (m, 4H), 7.59–7.54 (m, 4H), 7.29 (m, 2H), 1.72 (s, 18H). 13C NMR (101 MHz, CDCl3) δ (ppm) 153.1, 142.0, 139.9, 132.4, 129.1, 125.1, 119.4, 34.3, 29.2. HRMS (ESI): m/z [M + H]+ calcd. for C26H29N6: 425.2448; found: 425.2441.
  • 3,7-Di-tert-butyl-1,5-bis(3,5-dimethylphenyl)-1,5-dihydrodipyrazolo [3,4-b:3′,4′-e] pyrazine (3s), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 10:1), 20 mg, 42%, yellow solid, m.p.: 262–263 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.10 (s, 4H), 6.94 (s, 2H), 2.47 (s, 12H), 1.72 (s, 18H). 13C NMR (126 MHz, CDCl3) δ (ppm) 152.8, 141.9, 139.7, 138.8, 132.2, 126.8, 117.3, 34.2, 29.1, 21.7. HRMS (ESI): m/z [M + H]+ calcd. for C30H37N6: 481.3074; found: 481.3070.
  • (E)-1,2-bis(3-methyl-1-phenyl-1H-pyrazol-5-yl)diazene (4a), (silica gel: 200–300 mesh, solvent system: petroleum ether/ethyl acetate = 8:1), 14 mg, 40%, orange solid, m.p.: 198–199 °C. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.70 (d, J = 7.5 Hz, 4H), 7.50 (t, J = 7.5 Hz, 4H), 7.40 (t, J = 7.5 Hz, 2H), 6.40 (s, 2H), 2.39 (s, 6H). 13C NMR (126 MHz, CDCl3) δ (ppm) 154.3, 150.0, 139.0, 128.8, 127.5, 124.8, 94.6, 14.0. HRMS (ESI): m/z [M + H]+ calcd. for C20H19N6: 343.1666; found: 343.1663.
  • (1-Cyclopropylvinyl)benzene (5), (silica gel: 200–300 mesh, solvent system: petroleum ether), 20 mg, 70%, white solid. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.58 (d, J = 6.0 Hz, 2H), 7.31 (t, J = 7.0 Hz, 2H), 7.26 (d, J = 7.5 Hz, 1H), 5.26 (s, 1H), 4.92 (s, 1H), 1.63 (m, 1H), 0.83–0.79 (m, 2H), 0.58 (dd, J = 5.5, 2.2 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ (ppm) 149.3, 141.6, 128.1, 127.4, 126.1, 109.0, 15.6, 6.6. HRMS (ESI): m/z [M + H]+ calcd. for C11H13: 145.1012; found: 145.1008.

4. Conclusions

In summary, we have developed a concise protocol for the synthesis of dipyrazole-fused pyridazines and pyrazines via C-H/C-H, C-H/N-H, and N-H/N-H direct coupling from simple 5-aminopyrazoles. The mechanism investigations uncovered that the reaction involved the radical dimerization of 5-aminopyrazoles. The protocol exhibits broad substrate scope and high functional group compatibility. In addition, the preliminary fluorescence results suggest that dipyrazole-fused pyridazines and pyrazines may have some potential applications in materials chemistry.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules30020381/s1. Tables S1–S7, Scheme S1–S12 and Figures S1–S14: X-ray crystal structure and crystallographic data; optimization of reaction conditions; and characterization data for product 2a–2p, 3a–3m, 3q–3s, 4a, and 5, including 1H-NMR and 13C-NMR, see references [49,50,51].

Author Contributions

Conceptualization, Y.-P.Z.; methodology, Y.-P.Z.; investigation, Y.-X.C., J.-J.R., Y.-M.L., Y.-C.B., Q.-Q.Z., Y.-Z.Z., X.Y., X.-H.Z. and X.-S.Z.; data collection and curation, Y.-X.C., J.-J.R. and Y.-M.L.; writing—original draft preparation, Y.-X.C. and J.-J.R.; writing—review and editing, Y.-P.Z., A.-X.W. and Y.-Y.S.; visualization, Y.-X.C. and J.-J.R.; supervision, Y.-P.Z., A.-X.W. and Y.-Y.S.; project administration, Y.-P.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Shandong Provincial Natural Science Foundation (ZR2024MB054), Yantai “Double Hundred Plan”, and the Foundation of International Innovation Center for Forest Chemicals and Materials Nanjing Forestry University.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the article and Supplementary Materials.

Acknowledgments

The authors thank the Talent Induction Program for Youth Innovation Teams in Colleges and Universities of Shandong Province.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Kumar, A.; Singh, A.-K.; Singh, H.; Vijayan, V.; Kumar, D.; Naik, J.; Thareja, S.; Yadav, J.-P.; Pathak, P.; Grishina, M.; et al. Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective. Pharmaceuticals 2023, 16, 299. [Google Scholar] [CrossRef] [PubMed]
  2. Chen, Y.; Song, W.; Shen, L.; Qiu, N.; Hu, M.; Liu, Y.; Liu, Q.; Huang, L. Vasodilator Hydralazine Promotes Nanoparticle Penetration in Advanced Desmoplastic Tumors. ACS Nano 2019, 13, 1751–1763. [Google Scholar] [CrossRef]
  3. Komendantova, A.-S.; Fakhrutdinov, A.-N.; Menchikov, L.-G.; Sukhorukov, A.-Y.; Zavarzin, I.-V.; Volkova, Y.-A. Cyclization of β-Chlorovinyl Thiohydrazones into Pyridazines: A Mechanistic Study. Eur. J. Org. Chem. 2019, 2019, 527–536. [Google Scholar] [CrossRef]
  4. Grote, R.; Chen, Y.; Zeeck, A.; Antibiotics, J. Metrabolic Products of Microorganisms. J. Antibiot. 1988, 41, 595–601. [Google Scholar] [CrossRef] [PubMed]
  5. Scott, E.-N.; Meinhardt, G.; Jacques, C.; Laurent, D.; Thomas, A.-L. Vatalanib: The clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours. Expert Opin. Investig. Drugs 2007, 16, 367–379. [Google Scholar] [CrossRef]
  6. Cao, J.; Miao, Q.; Miao, S.; Bi, L.; Zhang, S.; Yang, Q.; Zhou, X.; Zhang, M.; Xie, Y.; Zhang, J.; et al. Tetramethylpyrazine (TMP) exerts antitumor effects by inducing apoptosis and autophagy in hepatocellular carcinoma. Int. Immunopharmacol. 2015, 26, 212–220. [Google Scholar] [CrossRef]
  7. De Wang, X.; Li, T.; Li, Y.; Yuan, W.-H.; Zhao, Y.-Q. 2-Pyrazine-PPD, a novel dammarane derivative, showed anticancer activity by reactive oxygen species-mediate apoptosis and endoplasmic reticulum stress in gastric cancer cells. Eur. J. Pharmacol. 2020, 881, 173211. [Google Scholar] [CrossRef]
  8. Łagocka, R.; Dziedziejko, V.; Kłos, P.; Pawlik, A. Favipiravir in Therapy of Viral Infections. J. Clin. Med. 2021, 10, 273. [Google Scholar] [CrossRef]
  9. Takeo, F.; Hiroyoshi, D.; Kazuhiro, W.; Hideo, I.; Masakazu, M.; Minoru, N.; Nobuyoshi, S. Antitumor effects and drug interactions of the proteasome inhibitor bortezomib (PS341) in gastric cancer cells. Anti-Cancer Drugs 2007, 18, 677–686. [Google Scholar] [CrossRef]
  10. Henry, M.; Mostafa, M.; Sutherland, A. Recent Advances in Transition-Metal-Catalyzed, Directed Aryl C–H/N–H Cross-Coupling Reactions. Synthesis 2017, 49, 4586–4598. [Google Scholar] [CrossRef]
  11. Bansal, S.; Shabade, A.-B.; Punji, B. Advances in C(sp2) − H/C(sp2) − H Oxidative Coupling of (Hetero)arenes Using 3d Transition Metal Catalysts. Adv. Synth. Catal. 2021, 363, 1998–2022. [Google Scholar] [CrossRef]
  12. Giri, R.; Shi, B.-F.; Engle, K.M.; Maugel, N.; Yu, J.-Q. Transition metal-catalyzed C–H activation reactions: Diastereoselectivity and enantioselectivity. Chem. Soc. Rev. 2009, 38, 3242–3272. [Google Scholar] [CrossRef] [PubMed]
  13. Yang, L.-F.; Zeng, L.; Zhu, Y.-P.; Li, J.-H. Copper-catalyzed photoredox 1,4-amidocyanation of 1,3-enynes with N-amidopyridin-1-ium salts and TMSCN: Facile access to α-amido allenyl nitriles. Chin. Chem. Lett. 2024, 35, 109685. [Google Scholar] [CrossRef]
  14. Han, X.-L.; Lin, P.-P.; Li, Q.-J. Recent advances of allenes in the first-row transition metals catalyzed C-H activation reactions. Chin. Chem. Lett. 2019, 30, 1495–1502. [Google Scholar] [CrossRef]
  15. Yi, R.-N.; He, W.-M. Photoinduced bismuth vanadate-catalyzed C(sp2)-H functionalization. Chin. Chem. Lett. 2025, 35, 109253. [Google Scholar] [CrossRef]
  16. Gambouz, K.; Abbouchi, A.-E.; Nassiri, S.; Suzenet, F.; Bousmina, M.; Akssira, M.; Guillaumet, G.; El Kazzouli, S. Palladium-Catalyzed Oxidative Arylation of 1H-Indazoles with Arenes. Eur. J. Org. Chem. 2020, 48, 7435–7439. [Google Scholar] [CrossRef]
  17. Chen, C.; Chen, X.; Zhao, H.; Jiang, H.; Zhang, M. Direct Access to Nitrogen Bi-heteroarenes via Iridium-Catalyzed Hydrogen-Evolution Cross-Coupling Reaction. Org. Lett. 2017, 19, 3390–3393. [Google Scholar] [CrossRef]
  18. Cao, L.; Zhao, H.; Guan, R.; Jiang, H.; Dixneuf, P.-H.; Zhang, M. Practical iridium-catalyzed direct α-arylation of N-heteroarenes with (hetero)arylboronic acids by H2O-mediated H2 evolution. Nat. Commun. 2021, 12, 4206. [Google Scholar] [CrossRef]
  19. Zhao, S.; Yuan, J.; Li, Y.-C.; Shi, B.-F. Copper-catalyzed oxidative C–H/C–H cross-coupling of benzamides and thiophenes. Chem. Commun. 2015, 51, 12823–12826. [Google Scholar] [CrossRef]
  20. Zhao, H.; Li, X.; Guan, R.; Jiang, H.; Zhang, M. Synthesis of Diverse Functionalized Quinoxalines by Oxidative Tandem Dual C−H Amination of Tetrahydroquinoxalines with Amines. Chem. Eur. J. 2019, 25, 15858–15862. [Google Scholar] [CrossRef] [PubMed]
  21. Yu, Q.; Fu, Y.; Huang, J.; Qin, J.; Zuo, H.; Wu, Y.; Zhong, F. Enantioselective Oxidative Phenol-Indole [3+2] Coupling Enabled by Biomimetic Mn(III)/Brønsted Acid Relay Catalysis. ACS Catal. 2019, 9, 7285–7291. [Google Scholar] [CrossRef]
  22. Zhang, L.-B.; Zhu, M.-H.; Du, W.-B.; Ni, S.-F.; Wen, L.-R.; Li, M. Silver-promoted regioselective [4+2] annulation reaction of indoles with alkenes to construct dihydropyrimidoindolone scaffolds. Chem. Commun. 2019, 55, 14383–14386. [Google Scholar] [CrossRef]
  23. Tian, S.-H.; Luo, T.; Zhu, Y.-P.; Wan, J.-P. Recent advances in the diversification of chromones and flavones by direct C-H bond activation or functionalization. Chin. Chem. Lett. 2020, 31, 3073–3082. [Google Scholar] [CrossRef]
  24. Varaksin, M.; Moseev, T.; Chupakhin, O.; Charushin, V.; Trofimov, B. Metal-free C–H functionalization of 2H-imidazole 1-oxides with pyrrolyl fragments in the design of novel azaheterocyclic ensembles. Org. Biomol. Chem. 2017, 15, 8280–8284. [Google Scholar] [CrossRef]
  25. Badigenchala, S.; Sekar, G. NIS Mediated Cross-Coupling of C(sp2)–H and N–H Bonds: A Transition-Metal-Free Approach toward Indolo[1,2-a]quinazolinones. J. Org. Chem. 2017, 82, 7657–7665. [Google Scholar] [CrossRef] [PubMed]
  26. Shakoor, S.-M.-A.; Mandal, S.-K.; Sakhuja, R. An Articulate Oxidative Transition-Metal-Free Homocoupling of Imidazo Heterocycles through C(sp2)–C(sp2) Bond Formation. Eur. J. Org. Chem. 2017, 2017, 2596–2602. [Google Scholar] [CrossRef]
  27. Dai, M.; Zhang, Y.; Zhang, X.; Wang, R.; Wei, W.; Zhang, Z.; Liang, T. Iodine-Mediated C2,3–H Aminoheteroarylation of Indoles. J. Org. Chem. 2023, 88, 15106–15117. [Google Scholar] [CrossRef]
  28. Li, Y.-X.; Ji, K.-G.; Wang, H.-X.; Ali, S.; Liang, Y.-M. Iodine-Induced Regioselective C−C and C−N Bonds Formation of N-Protected Indoles. J. Org. Chem. 2011, 76, 744–747. [Google Scholar] [CrossRef]
  29. Wu, Y.-C.; Jiang, S.-S.; Song, R.-J.; Li, J.-H. A metal- and oxidizing-reagent-free anodic para-selective amination of anilines with phenothiazines. Chem. Commun. 2019, 55, 4371–4374. [Google Scholar] [CrossRef]
  30. Wang, Y.; Tian, B.; Ding, M.; Shi, Z. Electrochemical Cross-Dehydrogenative Coupling between Phenols and β-Dicarbonyl Compounds: Facile Construction of Benzofurans. Chem. Eur. J. 2020, 26, 4297–4303. [Google Scholar] [CrossRef] [PubMed]
  31. Feng, P.; Ma, G.; Chen, X.; Wu, X.; Lin, L.; Liu, P.; Chen, T. Electrooxidative and Regioselective C−H Azolation of Phenol and Aniline Derivatives. Angew. Chem. Int. Ed. 2019, 58, 8400–8404. [Google Scholar] [CrossRef] [PubMed]
  32. Luo, M.-J.; Li, Y.; Ouyang, X.-H.; Li, J.-H.; He, D.-L. Electrochemical dehydrogenative cross-coupling of two anilines: Facile synthesis of unsymmetrical biaryls. Chem. Commun. 2020, 56, 2707–2710. [Google Scholar] [CrossRef] [PubMed]
  33. Xie, L.-Y.; Hu, J.-L.; Song, Y.-X.; Jia, G.-K.; Lin, Y.-W.; He, J.-Y.; Cao, Z.; He, W.-M. Visible-Light-Initiated Cross-Dehydrogenative Coupling of Quinoxalin-2(1H)-ones and Simple Amides with Air as an Oxidant. ACS Sustain. Chem. Eng. 2019, 7, 19993–19999. [Google Scholar] [CrossRef]
  34. Qin, J.-H.; Luo, M.-J.; An, D.-L.; Li, J.-H. Electrochemical 1,2-Diarylation of Alkenes Enabled by Direct Dual C–H Functionalizations of Electron-Rich Aromatic Hydrocarbons. Angew. Chem. Int. Ed. 2021, 60, 1861–1868. [Google Scholar] [CrossRef]
  35. Yu, Y.; Yuan, Y.; Liu, H.; He, M.; Yang, M.; Liu, P.; Yu, B.; Dong, X.; Lei, A. Electrochemical oxidative C–H/N–H cross-coupling for C–N bond formation with hydrogen evolution. Chem. Commun. 2019, 55, 1809–1812. [Google Scholar] [CrossRef]
  36. Liu, K.; Wu, J.; Deng, Y.; Song, C.; Song, W.; Lei, A. Electrochemical C−H/N−H Oxidative Cross Coupling of Imidazopyridines with Diarylamines to Synthesize Triarylamine Derivatives. ChemElectroChem 2019, 6, 4173–4176. [Google Scholar] [CrossRef]
  37. Song, C.; Liu, K.; Jiang, X.; Dong, X.; Weng, Y.; Chiang, C.-W.; Lei, A. Electrooxidation Enables Selective Dehydrogenative [4+2] Annulation between Indole Derivatives. Angew. Chem. Int. Ed. 2020, 59, 7193–7197. [Google Scholar] [CrossRef]
  38. Jiang, B.; Ning, Y.; Fan, W.; Tu, S.-J.; Li, G. Oxidative Dehydrogenative Couplings of Pyrazol-5-amines Selectively Forming Azopyrroles. J. Org. Chem. 2014, 79, 4018–4024. [Google Scholar] [CrossRef]
  39. Ryan, M.C.; Martinelli, J.R.; Stahl, S.-S. Cu-Catalyzed Aerobic Oxidative N–N Coupling of Carbazoles and Diarylamines Including Selective Cross-Coupling. J. Am. Chem. Soc. 2018, 140, 9074–9077. [Google Scholar] [CrossRef] [PubMed]
  40. Hou, Z.-W.; Xu, H.-C.; Wang, L. Electrochemical dehydrogenative N–H/N–H coupling reactions. Curr. Opin. Electrochem. 2022, 34, 100988. [Google Scholar] [CrossRef]
  41. Li, J.; Ma, Y.; Zhang, C.; Zhang, C.; Ma, H.; Guo, Z.; Liu, N.; Xu, M.; Ma, H.; Qiu, J. Green electrosynthesis of 3,3′-diamino-4,4′-azofurazan energetic materials coupled with energy-efficient hydrogen production over Pt-based catalysts. Nat. Commun. 2023, 14, 8146. [Google Scholar] [CrossRef] [PubMed]
  42. Lv, S.; Han, X.; Wang, J.-Y.; Zhou, M.; Wu, Y.; Ma, L.; Niu, L.; Gao, W.; Zhou, J.; Hu, W.; et al. Tunable Electrochemical C−N versus N−N Bond Formation of Nitrogen-Centered Radicals Enabled by Dehydrogenative Dearomatization: Biological Applications. Angew. Chem. Int. Ed. 2020, 59, 11583–11590. [Google Scholar] [CrossRef]
  43. Luo, B.-K.; Dong, W.-F.; Ma, Q.-J.; Yang, H.; Tang, W.-J. Synthesis of Biheteroaryls by Pd-Catalyzed Homocoupling of Heteroaryl Bromides. Org. Lett. 2024, 26, 8736–8740. [Google Scholar] [CrossRef] [PubMed]
  44. Rastogi, G.-K.; Deb, M.-L.; Baruah, P.-K. Copper-catalysed dehydrogenative self-coupling/cyclization of 5-aminopyrazoles: Synthesis and photophysical study of pyridazines. Chem. Commun. 2023, 59, 9642–9645. [Google Scholar] [CrossRef]
  45. CCDC 2322498, 2322499, 2322519 Contain the Supplementary Crystallographic Data for this Paper. Available online: www.ccdc.cam.ac.uk/data_request/cif (accessed on 29 October 2024).
  46. Wang, Y.-F.; Zhu, X.; Chiba, S. Copper-Catalyzed Aerobic [3+2]-Annulation of N-Alkenyl Amidines. J. Am. Chem. Soc. 2012, 134, 3679–3682. [Google Scholar] [CrossRef] [PubMed]
  47. Wang, Y.-F.; Chen, H.; Zhu, X.; Chiba, S. Copper-Catalyzed Aerobic Aliphatic C–H Oxygenation Directed by an Amidine Moiety. J. Am. Chem. Soc. 2012, 134, 11980–11983. [Google Scholar] [CrossRef]
  48. Wang, Y.-F.; Zhang, F.-L.; Chiba, S. Oxidative Radical Skeletal Rearrangement Induced by Molecular Oxygen: Synthesis of Quinazolinones. Org. Lett. 2013, 15, 2842–2845. [Google Scholar] [CrossRef] [PubMed]
  49. Cao, J.; Lv, D.; Yu, F.; Chiou, M.-F.; Li, Y.; Bao, H. Regioselective Three-Component Synthesis of Vicinal Diamines via 1,2-Diamination of Styrenes. Org. Lett. 2021, 23, 3184–3189. [Google Scholar] [CrossRef]
  50. Yan, M.; Zhu, L.; Zhang, X.; Yin, S.-F.; Kambe, N.; Qiu, R. Nickel-Catalyzed N, N-Diarylation of 8-Aminoquinoline with Large Steric Aryl Bromides and Fluorescence of Products. Org. Lett. 2021, 23, 2514–2520. [Google Scholar] [CrossRef]
  51. Yang, T.; Cao, X.; Zhang, X.-X.; Ou, Y.; Au, C.-T.; Yin, S.-F.; Qiu, R. Iodine-Catalyzed Synthesis of N, N′-Chelate Organoboron Aminoquinolate. J. Org. Chem. 2020, 85, 12430–12443. [Google Scholar] [CrossRef]
Molecules 30 00381 g001
Figure 1. Selected examples of bioactive pyridazines (A1–A4) and pyrazines (A5–A8) containing molecules.
Figure 1. Selected examples of bioactive pyridazines (A1–A4) and pyrazines (A5–A8) containing molecules.
Molecules 30 00381 g001
Molecules 30 00381 sch001
Scheme 1. The reported strategies for the synthesis of C(sp2)-C(sp2)/C(sp2)-N/N-N bonds via cross dehydrogenative coupling (a–f) and this work (g).
Scheme 1. The reported strategies for the synthesis of C(sp2)-C(sp2)/C(sp2)-N/N-N bonds via cross dehydrogenative coupling (a–f) and this work (g).
Molecules 30 00381 sch001
Molecules 30 00381 g002
Figure 2. Scope of dipyrazole-fused pyridazines. Reaction conditions: 1a (0.2 mmol), Cu(OAc)2 (3.0 equiv.), benzoyl peroxide (BPO) (0.5 equiv.), and K2S2O8 (2.5 equiv.) in toluene at 100 °C for 10 h. Isolated yields provided.
Figure 2. Scope of dipyrazole-fused pyridazines. Reaction conditions: 1a (0.2 mmol), Cu(OAc)2 (3.0 equiv.), benzoyl peroxide (BPO) (0.5 equiv.), and K2S2O8 (2.5 equiv.) in toluene at 100 °C for 10 h. Isolated yields provided.
Molecules 30 00381 g002
Molecules 30 00381 g003
Figure 3. Scope of dipyrazole-fused pyrazines. Reaction conditions: 1a (0.2 mmol), CuCl2 (20 mol%), 1,10-phenanthroline (0.3 equiv.), tert-butyl peroxybenzoate (0.5 equiv.), and Na2CO3 (2.5 equiv.) in toluene at 130 °C for 12 h. Isolated yields provided.
Figure 3. Scope of dipyrazole-fused pyrazines. Reaction conditions: 1a (0.2 mmol), CuCl2 (20 mol%), 1,10-phenanthroline (0.3 equiv.), tert-butyl peroxybenzoate (0.5 equiv.), and Na2CO3 (2.5 equiv.) in toluene at 130 °C for 12 h. Isolated yields provided.
Molecules 30 00381 g003
Molecules 30 00381 sch002
Scheme 2. Control experiments (a–f) and the scale-up reactions (g).
Scheme 2. Control experiments (a–f) and the scale-up reactions (g).
Molecules 30 00381 sch002
Molecules 30 00381 sch003
Scheme 3. Proposed mechanism.
Scheme 3. Proposed mechanism.
Molecules 30 00381 sch003
Molecules 30 00381 g004
Figure 4. Fluorescence spectra of compounds 2 in CH2Cl2 (1 × 10−5 M) under UV irradiation (285 nm).
Figure 4. Fluorescence spectra of compounds 2 in CH2Cl2 (1 × 10−5 M) under UV irradiation (285 nm).
Molecules 30 00381 g004
Molecules 30 00381 g005
Figure 5. Fluorescence spectra of compounds 3 in CH2Cl2 (1 × 10−5 M) under UV irradiation (285 nm).
Figure 5. Fluorescence spectra of compounds 3 in CH2Cl2 (1 × 10−5 M) under UV irradiation (285 nm).
Molecules 30 00381 g005
Molecules 30 00381 g006
Figure 6. The fluorescence emission spectra of 2a (left) and 3l (right) in CH2Cl2, toluene, ACN, CH3OH, and DMSO at a concentration of 1 × 10−5 mol/L.
Figure 6. The fluorescence emission spectra of 2a (left) and 3l (right) in CH2Cl2, toluene, ACN, CH3OH, and DMSO at a concentration of 1 × 10−5 mol/L.
Molecules 30 00381 g006
Molecules 30 00381 sch004
Scheme 4. General procedure for synthesis of 2a.
Scheme 4. General procedure for synthesis of 2a.
Molecules 30 00381 sch004
Molecules 30 00381 sch005
Scheme 5. General procedure for synthesis of 3a.
Scheme 5. General procedure for synthesis of 3a.
Molecules 30 00381 sch005
Table 1. Optimization studies for the preparation of 2a a,b. (a) Reaction conditions: 3-methyl-1-phenyl-1H-pyrazol-5-amine 1a (0.2 mmol) in solvent (2.0 mL) at different temperatures for 10 h under air in closed vial. (b) Isolated yields of 2a based on 1a. BPO = benzoyl peroxide, TBHP = tert-butyl hydroperoxide, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBPB = tert-butyl peroxy benzoate.
Table 1. Optimization studies for the preparation of 2a a,b. (a) Reaction conditions: 3-methyl-1-phenyl-1H-pyrazol-5-amine 1a (0.2 mmol) in solvent (2.0 mL) at different temperatures for 10 h under air in closed vial. (b) Isolated yields of 2a based on 1a. BPO = benzoyl peroxide, TBHP = tert-butyl hydroperoxide, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBPB = tert-butyl peroxy benzoate.
Molecules 30 00381 i001
EntryCatalysts
(Equiv.)		Oxidants
(Equiv.)		Additives
(Equiv.)		Temp
(℃)		SolventYield (%)
1Cu(OAc)2 (3.0) 100Toluene50
2Cu(OAc)2 (3.0)BPO (0.5) 100Toluene58
3Cu(OAc)2 (3.0)TBHP (0.5) 100Toluene52
4Cu(OAc)2 (3.0)DDQ (0.5) 100Toluene42
5Cu(OAc)2 (3.0)TBPB (0.5) 100Toluene38
6CuCl2(3.0)BPO (0.5) 100Toluene46
7CuBr (3.0)BPO (0.5) 100Toluene40
8CuI (3.0)BPO (0.5) 100Toluene38
9CuCl (3.0)BPO (0.5) 100Toluene42
10Cu(OAc)2.H2O (3.0)BPO (0.5) 100Toluene48
11Zn (OAc)2 (3.0)BPO (0.5) 100Toluene36
12FeCl3(3.0)BPO (0.5) 100Toluene12
13Cu(OAc)2 (3.0)BPO (0.5) 110Toluene55
14Cu(OAc)2 (3.0)BPO (0.5) 120Toluene53
15Cu(OAc)2 (3.0)BPO (0.5) 90Toluene51
16Cu(OAc)2 (3.0)BPO (0.5) 80Toluene44
17Cu(OAc)2 (2.0)BPO (0.5) 100Toluene56
18Cu(OAc)2 (1.0)BPO (0.5) 100Toluene48
19Cu(OAc)2 (3.0)BPO (0.25) 100Toluene55
20Cu(OAc)2 (3.0)BPO (0.75) 100Toluene53
21Cu(OAc)2 (3.0)BPO (0.5) 100DMSO50
22Cu(OAc)2 (3.0)BPO (0.5) 100Dioxane40
23Cu(OAc)2 (3.0)BPO (0.5) 100DEC42
24Cu(OAc)2 (3.0)BPO (0.5) 100MeCN40
25Cu(OAc)2 (3.0)BPO (0.5) 100DMF56
26Cu(OAc)2 (3.0)BPO (0.5)Na2CO3 (2.5)100Toluene54
27Cu(OAc)2 (3.0)BPO (0.5)Cs2CO3 (2.5)100Toluene41
28Cu(OAc)2 (3.0)BPO (0.5)K2S2O8 (2.5)100Toluene79
29Cu(OAc)2 (3.0)BPO (0.5)K2S2O8 (1.5)100Toluene60
30Cu(OAc)2 (3.0)BPO (0.5)K2S2O8 (3.5)100Toluene70
Table 2. Optimization studies for the preparation of 3a a,b. (a) Reaction conditions: 3-methyl-1-phenyl-1H-pyrazol-5-amine 1a (0.2 mmol) in solvent (2.0 mL) at different temperatures for 12 h under air in closed vial. (b) Isolated yields. BPO = benzoyl peroxide, TBHP = tert-butyl hydroperoxide, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBPB = tert-butyl peroxy benzoate, Bipy = 2,2-bipyridine, 1,10-phen = 1,10-phenanthroline.
Table 2. Optimization studies for the preparation of 3a a,b. (a) Reaction conditions: 3-methyl-1-phenyl-1H-pyrazol-5-amine 1a (0.2 mmol) in solvent (2.0 mL) at different temperatures for 12 h under air in closed vial. (b) Isolated yields. BPO = benzoyl peroxide, TBHP = tert-butyl hydroperoxide, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TBPB = tert-butyl peroxy benzoate, Bipy = 2,2-bipyridine, 1,10-phen = 1,10-phenanthroline.
Molecules 30 00381 i002
EntryCatalysts
(Equiv.)		Oxidants
(Equiv.)		Additives
(Equiv.)		Ligands
(Equiv.)		Temp
(℃)		SolventYield
(%)
1Cu(OAc)2 (20%) 130Toluene36
2Cu(OAc)2 (20%)BPO (0.5) 130Toluene38
3Cu(OAc)2 (20%)TBHP (0.5) 130Toluene37
4Cu(OAc)2 (20%)DDQ (0.5) 130Toluene32
5Cu(OAc)2 (20%)TBPB (0.5) 130Toluene41
6CuCl2 (20%)TBPB (0.5) 130Toluene47
7CuBr (20%)TBPB (0.5) 130Toluene40
8CuI (20%)TBPB (0.5) 130Toluene38
9CuCl (20%)TBPB (0.5) 130Toluene41
10Cu(OAc)2.H2O(20%)TBPB (0.5) 130Toluene43
11CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5) 130Toluene51
12CuCl2 (20%)TBPB (0.5)Cs2CO3 (2.5) 130Toluene34
13CuCl2 (20%)TBPB (0.5)tBuONa (2.5) 130Toluene36
14CuCl2 (20%)TBPB (0.5)KI (2.5) 130Toluene29
15CuCl2 (20%)TBPB (0.5)K2S2O8 (2.5) 130Toluene38
16CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5) 130Toluene48
17CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5) 130DMF35
18CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5) 130DMSO32
19CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5) 130NMP24
20CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5) 130Dioxane26
21CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5) 130DEC24
22CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5) 130DMAC21
23CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5)Bipy (0.3)130Toluene49
24CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5)1,10-Phen (0.3)130Toluene59
25CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5)1,10-Phen (0.3)120Toluene46
26CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5)1,10-Phen (0.3)100Toluene38
27CuCl2 (20%)TBPB (0.5)Na2CO3 (2.5)1,10-Phen (0.3)80Toluene29
28CuCl2 (40%)TBPB (0.5)Na2CO3 (2.5)1,10-Phen (0.3)130Toluene50
29CuCl2 (10%)TBPB (0.5)Na2CO3 (2.5)1,10-Phen (0.3)130Toluene35
Table 3. Photophysical properties of compound 2 in CH2Cl2 (1 × 10−5 M). a Absorption maximum. b Emission maximum. c Quinine sulfate was used as a standard for fluorescence QY = 0.54 (0.5 M H2SO4).
Table 3. Photophysical properties of compound 2 in CH2Cl2 (1 × 10−5 M). a Absorption maximum. b Emission maximum. c Quinine sulfate was used as a standard for fluorescence QY = 0.54 (0.5 M H2SO4).
Compd.λmax a (nm)λem b (nm)Stokes Shift (nm)ΦF c (%)
2a2795022233.0
2b266298325.2
2c2722952321.8
2d2733002710.3
2e238304662.2
2f274296229.0
2g3094921837.4
2h3124781667.6
2i2712942311.6
2j273300279.1
2k273293202.0
2l2712942312.6
2m2735112388.0
2n272296247.5
2o2775102335.8
2p274298242.0
Table 4. Photophysical properties of compound 3 in CH2Cl2 (1 × 10−5 M). a Absorption maximum. b Emission maximum. c Quinine sulfate was used as a standard for fluorescence QY = 0.54 (0.5 M H2SO4).
Table 4. Photophysical properties of compound 3 in CH2Cl2 (1 × 10−5 M). a Absorption maximum. b Emission maximum. c Quinine sulfate was used as a standard for fluorescence QY = 0.54 (0.5 M H2SO4).
Compd.λmax a (nm)λem b (nm)Stokes Shift (nm)ΦF c (%)
3a28450522114.0
3b3045011978.6
3c2845232395.3
3d2865302442.4
3e2855302451.7
3f2855222372.7
3g28549521013.8
3h2844962124.3
3i2874741879.2
3j274302286.2
3k2875442570.3
3l28450321912.3
3m2895342458.0
3q28449921514.3
3r28350021716.2
3s2855122275.9
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Chai, Y.-X.; Ren, J.-J.; Li, Y.-M.; Bai, Y.-C.; Zhang, Q.-Q.; Zhao, Y.-Z.; Yang, X.; Zhang, X.-H.; Zhang, X.-S.; Wu, A.-X.; et al. 5-Aminopyrazole Dimerization: Cu-Promoted Switchable Synthesis of Pyrazole-Fused Pyridazines and Pyrazines via Direct Coupling of C-H/N-H, C-H/C-H, and N-H/N-H Bonds. Molecules 2025, 30, 381. https://doi.org/10.3390/molecules30020381

AMA Style

Chai Y-X, Ren J-J, Li Y-M, Bai Y-C, Zhang Q-Q, Zhao Y-Z, Yang X, Zhang X-H, Zhang X-S, Wu A-X, et al. 5-Aminopyrazole Dimerization: Cu-Promoted Switchable Synthesis of Pyrazole-Fused Pyridazines and Pyrazines via Direct Coupling of C-H/N-H, C-H/C-H, and N-H/N-H Bonds. Molecules. 2025; 30(2):381. https://doi.org/10.3390/molecules30020381

Chicago/Turabian Style

Chai, Yi-Xin, Jun-Jie Ren, Yi-Ming Li, Yi-Cheng Bai, Qing-Qing Zhang, Yi-Zhen Zhao, Xue Yang, Xiao-Han Zhang, Xin-Shuang Zhang, An-Xin Wu, and et al. 2025. "5-Aminopyrazole Dimerization: Cu-Promoted Switchable Synthesis of Pyrazole-Fused Pyridazines and Pyrazines via Direct Coupling of C-H/N-H, C-H/C-H, and N-H/N-H Bonds" Molecules 30, no. 2: 381. https://doi.org/10.3390/molecules30020381

APA Style

Chai, Y.-X., Ren, J.-J., Li, Y.-M., Bai, Y.-C., Zhang, Q.-Q., Zhao, Y.-Z., Yang, X., Zhang, X.-H., Zhang, X.-S., Wu, A.-X., Zhu, Y.-P., & Sun, Y.-Y. (2025). 5-Aminopyrazole Dimerization: Cu-Promoted Switchable Synthesis of Pyrazole-Fused Pyridazines and Pyrazines via Direct Coupling of C-H/N-H, C-H/C-H, and N-H/N-H Bonds. Molecules, 30(2), 381. https://doi.org/10.3390/molecules30020381

Article Metrics

Back to TopTop