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13 January 2021

Synthesis of 6,7-Dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles by Azomethine Imine-Alkyne Cycloadditions Using Immobilized Cu(II)-Catalysts

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Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
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Author to whom correspondence should be addressed.
Molecules2021, 26(2), 400;https://doi.org/10.3390/molecules26020400
This article belongs to the Special Issue Recent Advances in the Synthesis, Functionalization and Applications of Pyrazole-Type Compounds I
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Abstract

A series of 12 silica gel-bound enaminones and their Cu(II) complexes were prepared and tested for their suitability as heterogeneous catalysts in azomethine imine-alkyne cycloadditions (CuAIAC). Immobilized Cu(II)–enaminone complexes showed promising catalytic activity in the CuAIAC reaction, but these new catalysts suffered from poor reusability. This was not due to the decoordination of copper ions, as the use of enaminone ligands with additional complexation sites resulted in negligible improvement. On the other hand, reusability was improved by the use of 4-aminobenzoic acid linker, attached to 3-aminopropyl silica gel via an amide bond to the enaminone over the more hydrolytically stable N-arylenamine C-N bond. The study showed that silica gel-bound Cu(II)–enaminone complexes are readily available and suitable heterogeneous catalysts for the synthesis of 6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles.

1. Introduction

1,3-Dipolar cycloadditions of azomethine imines are important reactions to obtain pyrazoles with variable degree of saturation [1,2]. Since the end of the 20th century, this field has gained much attention; most azomethine imines have been recognized as stable compounds that are easy to prepare, store, and handle [1,2]. In this context, 1-alkylidene-3-oxopyrazolidin-1-ium-2-ides (3-oxopyrazolidin-1-azomethine imines), accessible by condensation of 1,2-unsubstituted pyrazolidin-3-ones with aldehydes or ketones, have been extensively used for regio- and stereoselective synthesis of pyrazolo[1,2-a]pyrazoles (bicyclic pyrazolidinones). Bicyclic pyrazolidinones exhibit antibiotic [3,4,5] and anti-Alzheimer activity [6], as well as inhibition of lymphocyte-specific protein tyrosine kinase [7,8] and Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) [9]. The most prominent examples of bioactive bicyclic pyrazolidinones are Eli Lilly’s γ-lactam antibiotics, which exhibit antibiotic activity similar to that of penicillins and cephalosporins (Figure 1) [3,4,5]. These antibiotics are based on 6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole scaffold, which is accessible by [3 + 2] cycloaddition of 3-oxopyrazolidin-1-ium-2-ides to acetylenes [1,2]. In this context, copper-catalyzed azomethine imine-alkyne cycloadditions (CuAIAC) [1,2,10,11,12,13,14,15,16] provide easy access to 6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles in a regio- and stereoselective manner under mild conditions that are compliant with requirements of “click” chemistry (Figure 1) [17,18,19,20,21,22,23]. In contrast to the CuAAC reaction, which is catalyzed only by Cu(I), the azomethine imine analogue (CuAIAC) is also catalyzed by Cu(II) [10,11,12,24,25,26,27]. This is a major advantage in terms of catalyst scope and simplicity of workup as the use of reducing agent, such as sodium ascorbate, can be avoided when Cu(II) catalyst is used (Figure 1).
Figure 1. Examples of bioactive bicyclic pyrazolidinones (left) and CuAIAC reaction (right).
Alkyl 2-substituted-3-(dimethylamino)propenoates and related enaminones are readily available and stable enamino-masked β-keto aldehydes, which are useful 1,3-dielectrophilic reagents in synthetic organic chemistry. Acid-catalyzed reactions with N-, C-, and O-nucleophiles take place under mild conditions by substitution of the dimethylamino group to give β-functionalized propenoates. With ambident nucleophiles, enaminones undergo cyclization into different heterocyclic systems [28,29,30,31,32,33]. Enaminones are also used as alkenes in cycloaddition reactions [34,35,36,37,38] and as bidentate N, O ligands [39,40,41,42,43,44,45,46,47,48,49] and tetradentate acacen-type ligands [27,50,51,52,53,54] to coordinate metal ions.
In recent years, an important part of our ongoing research on the chemistry of 3-pyrazolidinones [55] has been focused on CuAIAC reactions catalyzed by Cu(0) [56,57], Cu(I) [58,59,60,61], and Cu(II) [27]. In extension, we were interested in the use of immobilized Cu(II) complexes with enaminone-type ligands attached to the solid support in CuAIAC reactions. In contrast to the rather extensive use of immobilized copper complexes in azide-alkyne cycloadditions (CuAAC) [62], their applications in CuAIAC reactions are almost unknown [26]. 3-Aminopropyl silica gel-immobilized Cu(II)-enaminone complexes would be easy to prepare via a transamination reaction [28,29,30,31,32,33,63,64], could serve as heterogeneous Cu(II) catalysts for the synthesis of pyrazolo[1,2-a]pyrazoles, and would complement well the known examples of heterogeneous Cu(0)- [41], Cu(I)- [65,66,67,68,69], and Cu(II)-catalysts [26] in the CuAIAC reaction. Herein, we report the results of this study confirming the suitability of these new enaminone-based heterogeneous copper catalysts in regioselective [3 + 2] cycloadditions of 1-benzylidene-5,5-dimethyl-3-oxopyrazolidin-1-ium-2-ides to methyl propiolate leading to methyl 1-aryl-7,7-dimethyl-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylates.

2. Results

2.1. Synthesis and Catalytic Activity of Silica Gel-Bound Cu–Enaminone Complexes 5a–g

First, the starting enaminones 2a–g were prepared from active methylene compounds 1a–g by treatment with N,N-dimethylformamide dimethylacetal (DMFDMA) or tert-butoxy-bis(dimethylamino)methane (TBDMAM) at 20–110 °C following literature procedure [27]. Next, the enaminones 2a–g were reacted with equimolar amount of 3-aminopropyl silica gel (3) in methanol for 48 h to give the immobilized enaminones 4a–g. Subsequent treatment of 4a–g with one equivalent of Cu(OAc)2·H2O in methanol at room temperature for 48 h then furnished the desired complexes 5a–g. The complex 3-Cu was prepared by treatment of 3 with Cu(OAc)2·H2O in methanol (Scheme 1). Absorption bands at around 1600 cm−1 (C = O/C = N) in the IR spectra of compounds 5a–h, the results of combustion analyses for compounds 5a–g, and the results of characterization of the catalyst 5f by SEM and EDX spectroscopy were in line with attachment of copper–enaminone complexes to 3 (For characterization details see the Supporting Information).
Scheme 1. Reaction conditions: (i) DMFDMA or TBDMAM, CH2Cl2 or toluene, 20–110 °C; (ii) 3-aminopropyl silica gel (3), MeOH, 20 °C, 48 h; (iii) Cu(OAc)2·H2O, MeOH, 20 °C, 48 h.
Compounds 5a–g and 3-Cu were then evaluated for their catalytic activity in [3 + 2] cycloaddition of (Z)-3,3-dimethyl-5-oxo-2-(3,4,5-trimethoxybenzylidene)pyrazolidin-2-ium-1-ide (6a) to methyl propiolate (7). The reaction was performed in CH2Cl2 at room temperature for 5 h with 30 mg (~20 mol%) catalyst loading (Table 1). Quantitative conversion was obtained only with 2-indanone-derived catalyst 5f (Table 1, entry 6), while the conversion above 50% was also obtained from related enamino ketone-derived catalysts 5d and 5e (Table 1, entries 4 and 5). Catalysts 5a–c and 5g were less active and the respective conversions ranged from 33% to 47% (Table 1, entries 1–3 and 7). Moderate activity of 3-Cu (Table 1, entry 8) was in line with complexation of Cu(OAc)2 to 3-aminopropyl silica gel (3), which itself was found inactive (Table 1, entry 9).
Table 1. Evaluation of catalytic activity of 5a–g, 3-Cu, and 3 in model cycloaddition reaction 1.
The most active catalyst 5f was tested further. The model reaction was carried out varying reaction time (1–3 h) and catalyst loading (10–30 mg). The results are presented in Table 2. In the presence of 30 mg of the catalyst, the conversion was around 50% after one hour, around 90% after two hours, and 100% after three hours (Table 2, entries 1–3). Complete conversion was also achieved with 25 mg and 20 mg of the catalyst (Table 2, entries 4 and 5), while further lowering of the catalyst loading to 15 mg (89%) and to 10 mg (61%) gave incomplete conversions (Table 2, entries 6 and 7).
Table 2. Evaluation of catalyst 5f in model cycloaddition reaction 1.
Next, the substrate scope was investigated using 20 mg (~13 mol%) of catalyst 5f in reactions with azomethine imines 6a–f (Scheme 2). After 3 h, only dipoles 6a and 6d were transformed quantitatively into the corresponding cycloadducts 8a and 8d, while conversions of other dipoles ranged from 23% to 95%. The highest conversions (95–100%) were obtained with 3,4,5-trimethoxyphenyl- (6a), phenyl- (6d), and 4-nitrophenyl-substituted dipole (6f), whereas poor conversions (23–29%) were observed with 4-methoxy- (6b), 4-methyl- (6c), and 4-chloro-substituted dipole (6e). Since closely related Cu0- and Cu+-catalyzed cycloadditions did not show any significant substrate dependence [56,57], incomplete conversions may seem surprising, yet they are explainable by much shorter reaction time (i.e., 12–48 h [56,57] vs. 3 h in the present case). Quantitative conversion of dipole 6e into cycloadduct 8e after 48 h was in line with this rationale (Scheme 2).
Scheme 2. The conversions in CuAIAC reactions of dipoles 6a–f with methyl propiolate (7) catalyzed by 20 mg (~13 mol%) of 5f. The conversions were determined by 1H NMR of the crude reaction mixtures.
To further explore the reaction scope, azomethine imine 6a was reacted also with nonpolar phenylacetylene in the presence of catalyst 5f under the above standard reaction conditions. This reaction gave no conversion, even after prolonged treatment for 150 h. This result indicated a limitation of the reaction scope to polar electron-poor alkynes.
Reusability of the catalyst 5f in the standard model reaction (6a + 7 → 8a, 3 h, 30 mg of 5f) was tested next. Much to our disappointment, the quantitative conversion in the first run dropped significantly in the second (29%) and the third run (5%) and the catalyst was inactive upon the third run (Figure 2). If poor reusability of catalyst 5f is explainable by decomplexation of copper ions from the heterogeneous ligand 4f, then reusability should be improved by stronger coordination of copper(II) to the ligand. Therefore, we decided to address the reusability issue by attaching stronger coordinating acacen ligands 9a,b [27,50,51,52,53,54,70] and pyridine-enaminone ligands 9c [71] to 3-aminopropyl silica gel (3).
Figure 2. Reusability of catalysts 5f (), 11a (), 11b (), 11c (), and 15 () in the model reaction 6a + 7 → 8a. The conversions were determined by 1H NMR.

2.2. Synthesis and Catalytic Activity of Silica Gel-Bound Cu–Enaminone Complexes 11a–c and 15

Bis-enaminone compounds 9a and 9b [70] (Scheme 3) contain two terminal N,N-(dimethyl)enaminone groups that enable transaminative attachment to 3-aminopropyl silica gel (3). Thus, treatment of 9a and 9b with 3 in methanol at room temperature afforded the immobilized acacen ligands 10a and 10b, which were subsequently reacted with Cu(OAc)2·H2O in methanol to furnish the desired immobilized Cu–acacen complexes 11a and 11b (Scheme 3). To obtain pyridine-type catalyst 11c, bis-enaminone ligand 9c [71], was reacted with 3-aminopropyl silica gel (3) to give silica gel-bound ligand 10c, followed by treatment with Cu(OAc)2·H2O in methanol to furnish the copper complex 11c (Scheme 3). Absorption bands at around 1600 cm−1 (C = O/C = N) in the IR spectra of compounds 11a–c and the combustion analyses for compounds 11a–c were in line with attachment of copper–enaminone complexes to 3 (For characterization details see the Supporting Information).
Scheme 3. Reaction conditions: (i) 3-aminopropyl silica gel (3), MeOH, 20 °C, 48 h; (ii) Cu(OAc)2·H2O, MeOH, 20 °C, 48 h.
With the desired new catalysts 11a–c in our hands, we first examined their catalytic activity in model cycloaddition (6a + 7 → 8a, Table 3). After 3 h in the presence of 30 mg (~20 mol%) of the catalyst 11, 1,2-ethylenediamine-based catalyst 11a showed only moderate performance (61% conversion, Table 3, entry 1), while activities of 1,2-phenylenediamine-based catalyst 11b and pyridine-based catalyst 11c (Table 3, entries 2 and 3) were similar to that of catalyst 5f (cf. Table 2, entry 3). Further evaluation of catalysts 11b and 11c in terms of catalyst loading (Table 3, entries 4–7) and reaction time (Table 3, entries 8–11) confirmed the performance of 11b and 11c, which was similar to that of catalyst 5f (cf. Table 2, entries 1–7).
Table 3. Catalytic activity of heterogeneous Cu(II) catalysts 11a–c in model reaction 1.
The substrate scope of catalysts 11a–c was then checked by measuring conversions in the reactions of azomethine imines 6a–f with methyl propiolate (7) in dichloromethane using ~13 mol% (20 mg) catalyst loading (Scheme 4). Quantitative conversions after 3 h were achieved only with dipole 6a in the presence of catalysts 11b and 11c, and with electron-poor dipole 6f, relatively good conversions above 80% were obtained with all three catalysts. The conversions after 3 h were low to moderate (15–69%) with dipoles 6b–e. For the most part, these results were in line with those obtained with catalyst 5f. Notably, also the less reactive dipole 6e underwent full conversion within 48 h with catalyst 11c (Scheme 4, cf. Scheme 3).
Scheme 4. The conversions in CuAIAC reactions of dipoles 6a–f with methyl propiolate (7) catalyzed by ~13 mol% of 11a–c. The conversions were determined by 1H NMR of the crude reaction mixtures.
To our disappointment, reusability tests for catalysts 11a–c in the standard model reaction (6a + 7 → 8a, 3 h, 30 mg of 11) revealed only minor improvement of reusability of catalysts 11a–c in comparison to catalyst 5f. Initially highly active catalysts 11b and 11c became inactive upon the third run (see Figure 2 at the end of Section 2.1). On the basis of these data, it became clear that decoordination of Cu(II) from the ligand was not the main reason for low reusability of 5f and 11a–c. We then considered that loss of catalytic activity could also be explainable by detachment of Cu(II)-enaminone complex from 3-aminopropyl silica gel (3), for example, through hydrolytic cleavage of the enamine C-N bond, as proposed in Scheme 5. Hydrolysis of enaminone complex 5 gives the complex 5′, which can release Cu(II)-1,3-dicarbonyl complex 5″ in solution through decoordination from aminopropyl silica gel 3.
Scheme 5. A plausible mechanism for detachment of Cu(II)-enaminone complex from 3.
According to the proposed mechanism, the use of hydrolytically more stable enamine C-N bond should reduce detachment of Cu(II)-enaminone complex from the solid support and, thus, improve reusability of the catalyst. To confirm this hypothesis, we prepared silica gel-bound enaminone 14 using 4-aminobenzoic acid (12) as a bifunctional linker, which was bound to 3-aminopropyl silica gel (3) via a robust amide bond and to the enaminone 2f through a stronger N-arylenamine C-N bond (Scheme 6) [28,29,30,31,32,33,63,64]. Acid-catalyzed transamination of 2f with 4-aminobenzoic acid (12) gave the carboxy-functionalized enaminone 13, which was amidated with 3 using 1,1′-carbonyldiimidazole (CDI) as activating reagent. Subsequent treatment of the silica gel-bound enaminone 14 with copper(II) acetate in methanol then furnished the desired catalyst 15 (Scheme 6). Absorption bands at around 1600 cm−1 (C = O/C = N) in the IR spectra of compound 15 and the combustion analyses for 15 were in line with attachment of copper–enaminone complex to 3 (For characterization details see the Supporting Information).
Scheme 6. Reaction conditions: (i) 4-aminobenzoic acid (12), 37% aq. HCl (1 equiv.), MeOH, 20 °C; (ii) CDI, MeCN, 20 °C, 1 h, then 3-aminopropyl silica gel (3), MeCN, 20 °C, 120 h; (iii) Cu(OAc)2·H2O, MeOH, 20 °C, 48 h.
Activity and reusability of catalysts 5f, 11a–c, and 15 were tested in the standard model reaction (6a + 7 → 8a, CH2Cl2, 20 °C, 3 h, 30 mg catalyst loading). The results are summarized in Figure 2. In the first run, quantitative conversion was obtained with catalysts 5f, 11b, 11c, and 15, while catalyst 11a gave only 61% conversion. The catalytic activity of 5f and 11b,c dropped significantly and they became practically inactive after the second run. Surprisingly, the initially least active catalyst 11a lost catalytic activity more slowly than analogues 5f and 11b,c and remained only weakly active in the fifth run. On the other hand, catalyst 15 gave a near quantitative conversion in the second run (94%), followed by a gradual decrease of catalytic activity leading to 31% conversion in the fifth run. Thus, the reusability of N-arylenaminone catalyst 15 was significantly better than that of N-alkylenaminone analogues 5 and 11 (Figure 2). This result was consistent with the hypothesis that the decrease of catalytic activity was largely due to the detachment of the copper-enaminone complex from the solid support by hydrolysis of the C-N bond of the enamine (cf. Scheme 5).

3. Conclusions

Transamination of enaminones 2a–g and bis-enaminones 9a–c with 3-aminopropyl silica gel (3) in methanol gives the corresponding silica gel-bound enaminones 4a–g and 10a–c. Subsequent treatment of the immobilized enaminones 4a–g and 10a–c with copper(II) acetate in methanol gives the corresponding silica gel-bound Cu(II) complexes 5a–g and 11a–c. Both reactions are general and take place with different types of enaminones 2 and 9 under mild conditions. The obtained copper(II) complexes 5a–g and 11a–c exhibit catalytic activity in azomethine imine-alkyne cycloadditions (CuAIAC). The 2-indanone-derived catalyst 5f and the bis-enaminone-derived catalysts 11b and 11c showed the most promising activity, unfortunately, with poor reusability. The main cause of the poor reusability appears to be hydrolytic cleavage of the Cu(II)-enaminone complex from the 3-aminopropyl silica gel (3), rather than decomplexation of the copper(II) ions from the ligand. This hypothesis was confirmed by the synthesis of a modified catalyst 15 with hydrolytically more stable enamine C-N bond of the enamine attached to 3-aminopropyl silica gel (3) via a robust amide bond. Catalyst 15 exhibited better reusability while still retaining the same catalytic activity as analogues 5 and 11. In conclusion, silica gel-bound Cu(II)-enaminone complexes 5, 11, and 15 are easily available heterogeneous catalysts for the regioselective synthesis of pyrazolo[1,2-a]pyrazoles via [3 + 2] cycloaddition of 3-pyrazolidinone-derived azomethine imines to terminal ynones.

4. Materials and Methods

4.1. General Information

All solvents and reagents were used as received. Melting points were determined on SRS OptiMelt MPA100—Automated Melting Point System (Stanford Research Systems, Sunnyvale, CA, USA). The 1H NMR, 13C NMR, and 2D NMR spectra were recorded in CDCl3 and DMSO-d6 as solvents using Me4Si as the internal standard on a Bruker Avance III UltraShield 500 plus instrument (Bruker, Billerica, MA, USA) at 500 MHz for 1H and at 126 MHz for 13C nucleus, respectively. IR spectra were recorded on a Bruker FTIR Alpha Platinum spectrophotometer (Bruker, Billerica, MA, USA). Microanalyses were performed by combustion analysis on a Perkin-Elmer CHN Analyzer 2400 II (PerkinElmer, Waltham, MA, USA). Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA). Parallel stirring was carried out on a Tehtnica Vibromix 313 EVT orbital shaker (400 rpm in all cases) (Domel, Železniki, Slovenia). Flash column chromatography was performed on silica gel (Silica gel 60, particle size: 0.035–0.070 mm, Sigma-Aldrich, St. Louis, MO, USA).
Active methylene compounds 1a–g, 3-aminopropyl silica gel (3) (for preparative chromatography, 40–63 µm, 0.9 mmol/g amino groups, pore size ~9 nm), 4-aminobenzoic acid (12), Cu(OAc)2·H2O, N,N-dimethylformamide dimethylacetal (DMFDMA, for synthesis, ≥96%), tert-butoxy-bis(dimethylamino)methane (TBDMAM, technical grade), and 1,1′-carbonyldiimidazole (CDI) are commercially available (Sigma-Aldrich). Enaminones 2a [72], 2b [73], 2c [74], 2d [75], 2e [76], 2f [77], and 2g [78], bis-enaminones 9a, 9b [70], and 9c [71], and azomethine imines 6a,f [79], 6b,e [80], 6c [81], and 6d [82] were prepared following the literature procedures.

4.2. Synthesis of 3-Aminopropyl Silica Gel-Bound Copper(II)-Catalyst 3-Cu

A mixture of 3-aminopropyl silica gel (3) (5.015 g, 4.5 mmol of amino group), Cu(OAc)2·H2O (903 mg, 4.5 mmol), and methanol (25 mL) was stirred at 20 °C for 48 h. The insoluble material was collected by filtration, washed carefully with methanol until the filtrate was colorless (around 10 × 5 mL), and air-dried to give the copper(II) catalyst 3-Cu. Blue powder (5.163 g).

4.3. General Procedure for the Synthesis of 3-Aminopropyl Silica Gel-Bound Copper(II) Catalysts 5a–g

Enaminone 2 (1.381 mmol) was added to a suspension of 3-aminopropyl silica gel (3) (1.534 g, 1.381 mmol of amino group) in methanol (4 mL) and the mixture was stirred at 20 °C for 48 h. The insoluble material was collected by filtration, washed with methanol until the filtrate was colorless (around 10 × 5 mL), and air-dried to give 4. The immobilized enaminone 4 was resuspended in methanol (8 mL), Cu(OAc)2·H2O (275 mg, 1.381 mmol) was added, and the mixture was stirred at room temperature for 48 h. The insoluble material was collected by filtration, washed carefully with methanol until the filtrate was colorless (around 10 × 5 mL), and air-dried to give the copper(II) catalyst 5. The following compounds were prepared in this manner:

4.3.1. Compound 5a

Prepared from 2a (934 mg, 4.5 mmol) and 3 (5.015 g, 4.5 mmol of amino group) in MeOH (15 mL); then Cu(OAc)2·H2O (903 mg, 4.5 mmol), MeOH (25 mL). Blue powder (5.392 g), νmax 1558 (C = O/C = N), 1418 cm−1.

4.3.2. Compound 5b

Prepared from 2b (1.119 g, 4.5 mmol) and 3 (5.015 g, 4.5 mmol of amino group) in MeOH (15 mL); then Cu(OAc)2·H2O (903 mg, 4.5 mmol), MeOH (25 mL). Blue powder (5.611 g), νmax 1558 (C = O/C = N), 1419 cm−1.

4.3.3. Compound 5c

Prepared from 2c (1.119 g, 4.5 mmol) and 3 (5.015 g, 4.5 mmol of amino group) in MeOH (15 mL); then Cu(OAc)2·H2O (903 mg, 4.5 mmol), MeOH (25 mL). Blue powder (5.415 g), νmax 1565 (C = O/C = N), 1418 cm−1.

4.3.4. Compound 5d

Prepared from 2d (366 mg, 1.4 mmol) and 3 (1.534 g, 1.4 mmol of amino group) in MeOH (4 mL); then Cu(OAc)2·H2O (275 mg, 1.4 mmol), MeOH (8 mL). Blue powder (1.643 g), νmax 1567 (C = O/C = N), 1416 cm−1.

4.3.5. Compound 5e

Prepared from 2e (366 mg, 1.4 mmol) and 3 (1.534 g, 1.4 mmol of amino group) in MeOH (4 mL); then Cu(OAc)2·H2O (275 mg, 1.4 mmol), MeOH (8 mL). Light brown powder (1.598 g), νmax 1565 (C = O/C = N), 1416 cm−1.

4.3.6. Compound 5f

Prepared from 2f (844 mg, 4.5 mmol) and 3 (5.015 g, 4.5 mmol of amino group) in MeOH (15 mL); then Cu(OAc)2·H2O (903 mg, 4.5 mmol), MeOH (25 mL). Dark brown powder (5.514 g), νmax 1606 (C = O/C = N), 1436 cm−1.

4.3.7. Compound 5g

Prepared from 2g (195 mg, 1.4 mmol) and 3 (1.534 g, 1.4 mmol of amino group) in MeOH (4 mL); then Cu(OAc)2·H2O (275 mg, 1.4 mmol), MeOH (8 mL). Blue powder (1.607 g), νmax 1565 (C = O/C = N), 1416 cm−1.

4.4. General Procedure for the Synthesis of Silica Gel-Bound Copper(II) Catalysts 11a–c

Bis-enaminone 9 (0.5 mmol) was added to a suspension of 3-aminopropyl silica gel (3) (1.111 g, 1 mmol of amino group) in methanol (4 mL) and the mixture was stirred at 20 °C for 48 h. The insoluble material was collected by filtration, washed with methanol until the filtrate was colorless (around 10 × 5 mL), and air-dried to give the silica gel-bound bis-enaminone 10. The immobilized enaminone 10 was resuspended in methanol (8 mL), Cu(OAc)2·H2O (200 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 48 h. The insoluble material was collected by filtration, washed carefully with methanol until the filtrate was colorless (around 10 × 5 mL), and air-dried to give the copper(II) catalyst 11. The following compounds were prepared in this manner:

4.4.1. Compound 11a

Prepared from 9a (100 mg, 0.2 mmol) and 3 (490 g, 0.4 mmol of amino group); then Cu(OAc)2·H2O (80 mg, 0.4 mmol). Brown powder (527 mg), νmax 1569 (C = O/C = N), 1411 cm−1.

4.4.2. Compound 11b

Prepared from 9b (200 mg, 0.4 mmol) and 3 (884 g, 0.8 mmol of amino group); then Cu(OAc)2·H2O (160 mg, 0.8 mmol). Green-blue powder (906 mg), νmax 1564 (C = O/C = N), 1417 cm−1.

4.4.3. Compound 11c

Prepared from 9c (322 mg, 0.56 mmol) and 3 (1.265 g, 1.12 mmol of amino group); then Cu(OAc)2·H2O (160 mg, 0.8 mmol). Brown powder (1.294 mg), νmax 1552 (C = O/C = N), 1414 cm−1.

4.5. Synthesis of 3-Aminopropyl Silica Gel-Bound Copper(II) Complex 15

4.5.1. (E)-4-{[(2-Oxo-2,3-dihydro-1H-inden-1-ylidene)methyl]amino}benzoic acid (13)

Enaminone 2f (374 mg, 2 mmol) was added to a mixture of 4-aminobenzoic acid (12) (274 mg, 2 mmol), methanol (10 mL), and 37% aq. HCl (0.15 mL, 1.8 mmol) and the mixture was stirred at room temperature for 12 h. The precipitate was collected by filtration and washed with methanol (2 × 5 mL) and diethyl ether (2 × 5mL) to give 13. Beige solid (385 mg, 69%); E/Z = 85:15; mp 263–264 °C (with slow decomposition above 200 °C); νmax/cm−1 (ATR) 3014, 2813, 1669 (C = O), 1594, 1566, 1424, 1261, 1180, 1199, 1092, 947, 848, 753, 713, 634; δH (500 MHz; DMSO-d6; Me4Si): major isomer 3.49 (2H, s), 7.09 (1H, td, J = 7.5, 1.1 Hz), 7.23–7.27 (2H, m), 7.52 (2H, d, J = 8.8 Hz), 7.67 (1H, d, J = 7.6 Hz), 7.92 (2H, d, J = 8.8 Hz), 8.39 (1H, d, J = 12.2 Hz), 11.03 (1H, d, J = 12.2 Hz), 12.74 (1H, s), minor isomer 3.46 (3H, s), 7.19 (1H, td, J = 7.5, 1.1 Hz), 7.23–7.27 (1H, m), 7.33 (2H, br d, J = 7.4 Hz), 7.48 (2H, br d, J = 8.8 Hz), 7.71 (1H, d, J = 13.4 Hz), 8.04 (1H, d, J = 7.4 Hz), 9.47 (1H, d, J = 13.3 Hz), 12.74 (1H, s); δC (126 MHz; DMSO-d6; Me4Si): major isomer 41.9, 111.5, 115.6, 117.6, 124.7, 124.8, 124.9, 126.9, 131.1, 134.3, 134.4, 140.0, 143.8, 166.8, 204.4, minor isomer 41.4, 112.8, 116.2, 121.9, 124.6, 124.7, 125.7, 126.8, 131.1, 131.8, 135.5, 138.2, 145.5, 166.9, 202.4; HRMS (ESI): MH+, found 280.0968 (MH+). [C17H14NO3]+ requires 280.0968; (found: C, 71.98; H, 4.24; N, 4.73. C17H13NO3·¼H2O requires C, 71.95; H, 4.79; N, 4.94%).

4.5.2. Synthesis of Silica Gel-Bound Enaminone 14

1,1′-Carbonyldiimidazole (85 mg, 0.52 mmol) was added to a stirred suspension of carboxylic acid 13 (140 mg, 0.5 mmol) in acetonitrile (5 mL) and the mixture was stirred at room temperature for 1 h. Then, 3-aminopropyl silica gel (3) (500 mg, 0.45 mmol of NH2 group) was added and the suspension was stirred at room temperature for 120 h. Ethanol (2 mL) was added and the insoluble material was collected by filtration using a short column with fritted bottom (d = 1.5 cm, l = 10 cm) and the functionalized silica gel 14 was washed with EtOH-MeCN (1:1, 3 × 5 mL), EtOH (2 × 5 mL), DMF (2 × 5 mL), EtOH (3 mL), and Et2O (2 × 5mL) and air-dried. Brown powder (536 mg, 31%, loading ~0.3 mmol/g); FT-IR (ATR): νmax 1603 (C = O/C = N) cm−1.

4.5.3. Synthesis of Silica Gel-Bound Copper(II) Catalyst 15

3-Enaminopropyl silica gel 14 (300 mg, ~0.1 mmol of the enaminone) was added to a solution of Cu(OAc)2·H2O (50 mg, 0.25 mmol) in methanol (10 mL) and the mixture was stirred at 20 °C for 48 h. The insoluble material was collected by filtration, washed carefully with methanol until the filtrate was colorless (around 5 × 5 mL), and air-dried to give the copper(II) catalyst 15. Brown powder (280 mg, 81%, loading ~0.3 mmol/g); FT-IR (ATR): νmax 1603 (C = O/C = N) cm−1.

4.6. Synthesis of Methyl 1-Aryl-7,7-dimethyl-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylates 8a–f by [3 + 2] Cycloadditions of Azomethine Imines 6a–f to Methyl Propiolate (7) in the Presence of Catalysts 3-Cu, 5, 11, and 15

4.6.1. Determination of Conversion. General Procedure A

Catalyst 3-Cu, 5, 11, or 15 (10–30 mg) was added to a mixture of azomethine imine 6a–f (25–37 mg [83], 0.125 mmol), methyl propiolate (7) (12.5 μL, 0.15 mmol), and CH2Cl2 (4 mL) and the mixture was stirred at room temperature for 1–5 h. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated in vacuo to give 8a–f and 1H NMR spectrum of the residue was measured in CDCl3 to determine the conversion. 1H NMR data of compounds 8a,f [79], 8d [56,84], and 8e [56] were in agreement with the literature data.

4.6.2. Determination of Reusability of Catalysts. General Procedure B

Catalyst 5, 11, or 15 (30 mg) was added to a mixture of azomethine imine 6a (37 mg, 0.125 mmol), methyl propiolate (7) (12.5 μL, 0.15 mmol), and CH2Cl2 (4 mL) and the mixture was stirred at room temperature for 3 h. Stirring was stopped, the catalyst was allowed to settle down for 2 min, and the supernatant was carefully decanted and filtered. Dichloromethane (4 mL) was added to the catalyst, the mixture was stirred for 2 min, the catalyst was allowed to settle down for 2 min, and the supernatant was carefully decanted and filtered. The catalyst was washed once more with dichloromethane (4 mL) as described above. The combined filtrate was evaporated in vacuo and 1H NMR spectrum of the residue was measured to determine conversion, while the washed catalyst was used in the next run.

4.6.3. Synthesis of 1-aryl-7,7-dimethyl-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylates 8b and 8c. General Procedure C

Catalyst 5f (120 mg) was added to a mixture of azomethine imine 6b or 6c (0.5 mmol), methyl propiolate (7) (50 μL, 0.6 mmol), and CH2Cl2 (5 mL) and the mixture was stirred at room temperature for 24 h. The catalyst was removed by filtration and washed with dichloromethane (3 mL). The combined filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (Et2O). Fractions containing the product 8 were combined and evaporated in vacuo to give 8b and 8c.
7,7-Dimethyl-1-(4-methoxyphenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (8b). Prepared from azomethine imine 6b (116 mg, 0.5 mmol), methyl propiolate (7) (50 μL, 0.6 mmol), and CH2Cl2 (4 mL). Yellow oil (74 mg, 47%); νmax/cm−1 (ATR) 2955, 1696 (C = O), 1599, 1511, 1444, 1408, 1371, 1323, 1200, 1173, 1099, 1031, 959, 824, 727; δH (500 MHz; CDCl3; Me4Si): 1.14 (3H, s), 1.22 (3H, s), 2.38 (1H, d, J = 15.7 Hz), 2.86 (1H, d, J = 15.7 Hz), 3.62 (3H, s), 3.79 (3H, s), 5.43 (1H, d, J = 1.3 Hz), 6.87 (2H, d, J = 8.7 Hz), 7.35 (2H, d, J = 8.7 Hz), 7.48 (1H, d, J = 1.3 Hz); δC (126 MHz; DMSO-d6; Me4Si): 19.1, 25.1, 49.6, 51.6, 55.3, 64.1, 64.4, 113.9, 117.1, 129.0, 129.3, 134.2, 159.3, 164.3, 166.5; HRMS (ESI): MH+, found 317.1493 (MH+). [C17H21N2O4]+ requires 317.1496.
7,7-Dimethyl-1-(4-methylphenyl)-5-oxo-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazole-2-carboxylate (8c). Prepared from azomethine imine 6c (98 mg, 0.45 mmol), methyl propiolate (7) (50 μL, 0.6 mmol), and CH2Cl2 (4 mL). Yellow solid (83 mg, 61%); mp 152–155 °C; νmax/cm−1 (ATR) 3082, 2946, 1731 (C = O), 1687 (C = O), 1601, 1514, 1323, 1275, 1225, 1192, 1120, 1099, 1039, 1007, 947, 818, 733; δH (500 MHz; CDCl3; Me4Si): 1.12 (3H, s), 1.19 (3H, s), 2.33 (3H, s), 2.38 (1H, d, J = 14.7 Hz), 2.82 (1H, d, J = 14.7 Hz), 3.58 (3H, s), 5.40 (1H, d, J = 1.2 Hz), 7.12 (2H, d, J = 7.8 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.46 (1H, d, J = 1.5 Hz); δC (126 MHz; DMSO-d6; Me4Si): 19.1, 21.3, 25.1, 49.5, 51.6, 64.4, 64.6, 117.0, 127.8, 129.2, 129.5, 137.6, 139.1, 164.3, 166.7; HRMS (ESI): MH+, found 301.1546 (MH+). [C17H21N2O3]+ requires 301.1547.
Following the above Procedure C, also known cycloadducts 8a,d–f were obtained in the following isolated yields: compound 8a (92%), 8d (89%), 8e (84%), and 8f (88%). Spectral data for compounds 8a [56,79], 8d [56,84], 8e [56], and 8f [56,79] were in agreement with the literature data.

Supplementary Materials

The following are available online, copies of 1H and 13C NMR spectra of new compounds 8b, 8c, and 13, copies of IR spectra of catalysts 5a–g, 11a–c, and 15.

Author Contributions

Individual contributions of the authors are the following: conceptualization, U.Š., D.S., and J.S.; methodology, U.Š., D.S., U.G., F.P., B.Š., and J.S.; validation, U.Š., D.S, U.G., F.P., B.Š., and J.S.; formal analysis, U.Š., D.S., and J.S.; investigation, U.Š., D.S., and J.S.; resources, U.G., F.P., B.Š., and J.S.; data curation, U.Š., D.S., U.G., F.P., B.Š., and J.S.; writing—original draft preparation, U.G., F.P., B.Š., and J.S.; writing—review and editing, U.Š., D.S, U.G., F.P., B.Š., and J.S.; supervision, U.G., F.P., B.Š., and J.S.; project administration, U.G., F.P., B.Š., and J.S.; funding acquisition, U.G., F.P., B.Š., and J.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Slovenian Research Agency (ARRS), research core funding No. P1-0179.

Data Availability Statement

The data presented in this study are available in the Supporting Information.

Acknowledgments

We thank EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, 1000 Ljubljana, Slovenia, for using BX FTIR spectrophotometer. We thank Marjan Marinšek, University of Ljubljana, for characterization of the catalyst 5f by SEM and EDX spectroscopy.

Conflicts of Interest

The authors declare no conflict of interest.

ample Availability

Samples of the compounds 5a–g, 8a–f, 11a–c, and 13–15 are available from the authors.

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