Introduction

Pyrazolones represent important structural motifs in heterocyclic chemistry and are found in many biologically active molecules used in the pharmaceutical and agrochemical industries. Pyrazolones show anti-tuberculosis [1], anti-viral [2], anti-hypertension [3], anti-oxidation [4], neuroprotection [5], anti-diabetic [6], anti-inflammatory [7], and anti-cancer [8] activities. They are also used as ligands [9] in complexes with catalytic activity. Some pyrazolones are used as wool, cotton, and silk dyes [10]. In addition, derivatives of sulfur heterocycles show significant biological and pharmaceutical activities [11]. 1,3-Dithiol-2-ylidenes derivatives have attracted much attention due to their excellent electron donation characteristics as a component in electronic materials [12, 13]. Also, sulfur-containing heterocycles such as 1,3-dithiole derivatives have been considered potential new substances due to their superconducting, optical, and electrical switching capabilities [14].

Various methods for preparing 1,3-dithiole derivatives have been published [15,16,17,18,19]. Among the dithiols, 1,4-dithiafulvenes bearing ester groups have attracted much attention as building blocks of electronic materials [20, 21]. The most common methods reported for the synthesis of 1,4-dithiafulvenes containing ester groups are the use of Wittig reaction between aldehydes or ketones with phosphonium salts [22,23,24]. These reactions are usually carried out at − 78 °C under argon atmosphere and in the presence of strong base such as butyl lithium. On the other hand, preparation of phosphonium salts also includes several steps [25]. In this study, we attempted to prepare 1,4-dithiafulvenes containing ester groups using ketene dithioacetal intermediates under easier conditions.

Ketene dithioacetals are used as efficient intermediates in the synthesis of 1,3-dithiol derivatives. Ketene dithioacetals can generate from the reaction between carbon nucleophile and carbon disulfide [26]. The reaction between ketene dithioacetals and dual electrophilic species such as dihaloalkanes [27, 28], or α-halo carbonyl compounds produce sulfur-containing heterocycles with two sulfur atoms [29, 30].

Laboratory studies show that the biological activities of bioactive molecules are usually recovered if two or more bioactive units are grouped in a single molecule [31]. Therefore, hybrid molecules of various heterocycles with pyrazolones contain more effective biological activities [32]. Edaravone (I) has practical medicinal effects on a variety of diseases, including cardiovascular diseases [33], and Lanoconazole (II) shows significant antifungal activity [34]. Besides that, the 1,4-dithiafulvene unit (III) has a strong electron-donating property [21,22,23,24, 35] and is frequently used as a donor unit in donor–acceptor systems (Fig. 1).

Fig. 1
figure 1

Structures of pyrazolone and sulfur-containing molecules applied in medicine (I, II) and 1,4-dithiafulvene unit (III) applied in the material industry

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Due to potential of sulfur-containing heterocycles and pyrazolones as mentioned above, we became interested in the synthesis of hybrid molecules containing pyrazolones and 1,4-dithiafulvenes. Following our research on the one-pot synthesis of new heterocyclic compounds [36,37,38,39] herein, we report the facile one-pot synthesis of pyrazolone-1,4-dithiafulvene hybrids 5 from the reactions between β-keto esters 1 or dialkyl acetylenedicarboxylates 2 with hydrazines 3, carbon disulfide, and dialkyl acetylenedicarboxylates 4 (Scheme 1).

Scheme 1
scheme 1

One-pot reaction for the synthesis of pyrazolone-1,4-dithiafulvene hybrids 5

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Results and discussion

Synthesis and optimization of reaction conditions

The one-pot reaction between ethyl acetoacetate 1a, phenyl hydrazine 3a, carbon disulfide, and dimethylacetylenedicarboxylate 4a was selected as a model reaction to produce pyrazolone-1,4-dithiafulvene hybrid 5a (Table 1). At first, the reaction was carried out in the water in the presence of two equimolar of Et3N at room temperature. The progress of the reaction was monitored by TLC. After compilation of the reaction, product 5a was separate as orange powder by filtration. The reaction yield was 25%. To optimize the reaction conditions, the reaction was carried out in the presence of various bases and solvents, and the results are collected in Table 1. As illustrated in Table 1, the reaction was not done in the presence of KOH, K2CO3, and pyridine in water, and the reaction yield in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) was negligible (Table 1, entries 1–5). Therefore, the Et3N was selected as the appropriate base for this reaction. The use of CH2Cl2 and EtOH as the solvent could not increase the reaction yield (Table 1, entries 6, 7). When the reaction was performed in THF or DMSO, the reaction yield increased, but the increase of reaction yield in acetonitrile was more significant (Table 1, entries 8–10). Further studies investigating the effect of temperature on the reaction yield showed that when the reaction was carried out in refluxing acetonitrile, the reaction yield was reduced because of the generation of complex by-products (Table 1, entry 11). Therefore, it is found that room temperature is the optimum temperature for the synthesis of pyrazolone-1,4-dithiafulvene hybrid 5a. In addition, the study of the effect of the amount of base on the reaction yield showed that the two equimolar of the base is the optimum amount of base for this reaction (Table 1, entries 10, 12–14).

Table 1 Optimization of the reaction conditions for the synthesis of compound 5a
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In this reaction, no detectable by-products were formed. In addition to the desired product, small amounts of acetonitrile-soluble dark materials were formed which were separated from the main product by filtration. To evaluate the scalability of the reaction, the model reaction was performed at double and quadruple scale in optimal conditions and no significant change in the reaction yield was observed.

Characterization of products

The structure of 5a was confirmed by FT-IR, 1H NMR, 13C NMR, Mass, and elemental analysis data. In the IR spectra of 5a, the peaks related to the stretching vibration of the ester carbonyl groups and S-C bonds appear in 1735 and 755 cm−1, respectively. In the 1H NMR spectrum of 5a, methyl protons of pyrazolone moiety appear at δ = 2.46 ppm. Two methyl groups of ester moieties appear at δ = 3.95 and 3.96 ppm. The aromatic protons of 5a showed two triplets at δ = 7.16 ppm (3JHH = 8.4 Hz) and δ = 7.40 ppm (3JHH = 8.2 Hz), and a doublet at δ = 7.99 ppm (3JHH = 8.5 Hz). In addition, in the 13C NMR spectra of 5a, two ester CO signals overlapped at 160.4 ppm, and the 13C NMR spectra of 5a revealed 14 distinct signals, indicating that the hypothesized structure is correct. The mass spectrum of compound 5a showed the molecular ion peak at 390 m/z, which was expected (See experimental section).

To confirm the generalizability of the reaction, compounds 5a-i were synthesized through the one-pot reaction between β-keto esters 1 or acetylenic esters 2, with hydrazines 3, CS2, and dialkyl acetylenedicarboxylates 4 in the presence of Et3N in CH3CN. The reactions proceeded well, and the products 5b-i were obtained with a good yield within 6 h (See Table 2).

Table 2 One-pot synthesis of pyrazolone-1,4-dithiafulvene hybrids 5a–i
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The proposed mechanism for this reaction is depicted in Scheme 2. Initially, the pyrazolone derivatives I were generated from the reaction of β-keto esters 1 or acetylenic esters 2, with hydrazine derivatives 3 [40, 41]. Subsequently, the tautomeric intermediates II and III were obtained by adding the in situ generated pyrazolone derivative I to CS2 in the presence of Et3N [42]. Following the Michel addition of sulfur anion of II or III to triple bound of acetylenic esters 4, resulting in the production of intermediate IV. Cyclization of intermediate IV through the second Michel addition, resulting in intermediate V [43]. Finally, intermediate V is then oxidized in the presence of air to produce product 5 spontaneously (Scheme 2).

Scheme 2
scheme 2

The proposed mechanism for the synthesis of pyrazolone-1,4-dithiafulvene hybrids 5

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To investigate the effect of atmospheric oxygen on the formation of the product 5a, the model reaction was performed under an argon atmosphere. In this case, TLC analysis showed that product 5a was not formed. This shows that atmospheric oxygen acts as an oxidant in this reaction.

Conclusion

In conclusion, we successfully presented a mild, facile, and one-pot method for the synthesis of new pyrazolone-1,4-dithiafulvene hybrids by using readily available starting materials through a one-pot reaction between β-keto esters or dialkyl acetylenedicarboxylates with hydrazines, carbon disulfide, and dialkyl acetylenedicarboxylates in good yields. A screening of the reaction conditions demonstrated that, performing this reaction at room temperature and in acetonitrile in the presence of two equivalents of triethylamine as a base, are the best ones. The good yields and the ease of workup procedure make it an appealing, practical, and acceptable one-pot method for producing functionalized pyrazolone-1,4-dithiafulvene hybrids.

Experimental section

General information

Dialkyl acetylendicarboxylate, hydrazines, carbon disulfide, β-keto esters, and all solvents were obtained from Merck (Germany) and were used without further purification. RF values refer to thin-layer chromatography (TLC) performed on silica gel 60 F254 aluminum-backed silica plates (Merck). Melting points were measured with a Stuart SMP-3 apparatus. IR spectra of products were measured with an FTIR Perkin Elmer RXI. NMR spectra were reported on a Varian Inova 500 MHz (500 MHz for 1H and 125 MHz for 13C) with CDCl3 as the solvent. Chemical shifts are given in ppm (δ) relative to internal TMS, and coupling constants (J) are reported in Hertz (Hz). Mass spectra were recorded with an Agilent 5977A Series MSD spectrometer operating at an ionization potential of 70 eV.

General procedure for the synthesis of products (5a-i), exemplified by 5a

A mixture of ethyl acetoacetate (1 mmol) with phenyl hydrazine (1 mmol) and Et3N (2 mmol) in CH3CN (5 mL) was stirred for 2 h at room temperature. After that, carbon disulfide (1.2 mmol) was added, and the mixture was stirred for 30 min. Then, dropwise additions of DMAD (1 mmol) were made, and the mixture was stirred for 6 h. Following that, the solvent was removed under reduced pressure, and the residue was washed with water to yield the pure product. The product was recrystallized in ethanol to achieve higher purity samples.

Dimethyl 2-(3-methyl-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5a)

Orange powder; yield: 0.25 g (64%); m.p. 200–201 ◦C. TLC RF = 0.65 (ethyl acetate/n-hexane = 3:7), IR (KBr, υ, cm−1): 1737 (CO2Me), 1526 (C=CS2), 1252 (C−O), 754 (S−C) cm−1. MS (EI): m/z (%) = 390 (M+, 100), 331 (40), 257 (27), 207 (17), 91 (17). 1H NMR (500 MHz, CDCl3): δ = 2.46 (s, 3H, N=CCH3), 3.95 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 7.16 (t, 1H, 3JHH = 7.4 Hz, CHpara), 7.4 (t, 2H, 3JHH = 7.2 Hz, CHmeta), 7.99 (d, 2H, 3JHH = 8.5 Hz, CHortho) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 16.6 (N=C–CH3), 54.1 and 54.2 (2OCH3), 112.9 (C=CS2), 118.7 (2CHortho), 124.8 (CHpara), 129.0 (2CHmeta), 131.2 and 137.5 (2 = C–CO2CH3), 138.7 (Cipso), 144.4 (C=N), 158.9 (S–C–S), 159.5 (N–C=O), 160.4 (2CO2CH3) ppm.

Diethyl 2-(3-methyl-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5b)

Orange powder; yield: 0.24 g (57%); m.p. 198–199 ◦C. TLC RF = 0.55 (ethyl acetate/n-hexane = 3:7), IR (KBr, υ, cm−1): 1735 (CO2Et), 1524 (C=CS2), 1238 (C−O), 755 (S−C) cm−1. MS (EI): m/z (%) = 418 (M+, 100), 345 (12), 215 (25), 185 (14), 91 (27), 28 (16). 1H NMR (500 MHz, CDCl3): δ = 1.40 (t, 6H, 3JHH = 7.1 Hz, 2CO2CH2CH3), 2.48 (s, 3H, N=CCH3), 4.41 (q, 4H, 3JHH = 7.1 Hz, 2CO2CH2CH3), 7.17 (t, 1H, 3JHH = 7.3 Hz, CHpara), 7.40 (t, 2H, 3JHH = 7.4 Hz, 2CHmeta), 7.99 (d, 2H, 3JHH = 8.0 Hz, 2CHortho) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 14.1 (2OCH2CH3), 16.6 (N=C–CH3), 63.8 (2OCH2), 112.7 (C=CS2), 118.6 (2CHortho), 124.8 (CHpara), 129.0 (2CHmeta), 131.4 and 137.5 (2=C–CO2CH3), 138.7 (Cipso), 144.5 (C=N), 158.5 (S–C–S), 158.6 (N–C=O), 159.1 (2CO2CH2CH3) ppm.

Dimethyl 2-(5-oxo-1,3-diphenyl-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5c)

Orange powder; yield: 0.24 g (53%); m.p. 207–209 ◦C. TLC RF = 0.6 (ethyl acetate/n-hexane = 3:7), IR (KBr, υ, cm−1): 1738 (CO2Me), 1501 (C=CS2), 1258 (C−O), 756 (S−C) cm−1. MS (EI): m/z (%) = 394 (M+-CO2Me, 100), 366 (11), 335 (12), 281 (13), 261 (17), 207 (28), 145 (39), 91 (13). 1H NMR (500 MHz, CDCl3): δ = 3.87 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 7.20 (t, 1H, 3JHH = 7.3 Hz, CHpara), 7.42 (t, 2H, 3JHH = 7.8 Hz, 2CHmeta), 7.54–7.60 (m, 5H, 5CH-Ar), 8.07 (d, 2H, 3JHH = 8.2 Hz, 2CHortho) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 53.7 and 53.8 (2OCH3), 111.1 (C=CS2), 118.8 (2CHortho), 124.9 (CHpara), 128.7 (4CHmeta), 129.1 (2CHortho), 130.1 (CHpara), 131.4 (=C–CO2CH3), 132.4 (Cipso), 135.9 (=C–CO2CH3), 138.4 (Cipso), 147.2 (C=N), 159.0 (S–C–S), 159.2 (N–C=O), 162.0 and 162.1 (2CO2CH3) ppm.

Diethyl 2-(5-oxo-1,3-diphenyl-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5d)

Orange powder; yield: 0.3 g (63%); m.p. 184–185 ◦C. TLC RF = 0.55 (ethyl acetate/n-hexane = 3:7), IR (KBr, υ, cm−1): 1729 (CO2Et), 1494 (C=CS2), 1244 (C−O), 756 (S−C) cm−1. MS (EI): m/z (%) = 480 (M+, 100), 407 (20), 310 (5), 277 (32), 247 (16), 145 (40), 91 (36). 1H NMR (500 MHz, CDCl3): δ = 1.32 (t, 3H, 3JHH = 7.1 Hz, CO2CH2CH3), 1.39 (t, 3H, 3JHH = 7.0 Hz, CO2CH2CH3), 4.33 (q, 2H, 3JHH = 7.1 Hz, OCH2), 4.39 (q, 2H, 3JHH = 7.0 Hz, OCH2), 7.20 (t, 1H, 3JHH = 7.3 Hz, CHpara), 7.42 (t, 2H, 3JHH = 7.8 Hz, 2CHmeta), 7.55–7.61 (m, 5H, 5CH-Ar), 8.08 (d, 2H, 3JHH = 8.2 Hz, 2CHortho) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 14.0 and 14.1 (2OCH2CH3), 63.4 and 63.5 (2OCH2), 111.2 (C=CS2), 119.0 (2CHortho), 125.1 (CHpara), 129.0 (4CHmeta), 129.3 (2CHortho), 130.3 (CHpara), 131.7 (=C–CO2CH3), 133.0 (Cipso), 136.1 (=C–CO2CH3), 138.7 (Cipso), 147.4 (C=N), 158.9 (S–C–S), 159.2 (N–C=O), 162.4 and 162.8 (2CO2CH3) ppm.

Dimethyl 2-(3-(methoxycarbonyl)-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5e)

Yellow powder; yield: 0.22 g (51%); m.p. 246–248 ◦C. TLC RF = 0.55 (ethyl acetate/n-hexane = 4:6), IR (KBr, υ, cm−1): 1753 and 1712 (CO2Me), 1487 (C=CS2), 1226 (C−O), 764 (S−C) cm−1. MS (EI): m/z (%) = 434 (M+, 100), 406 (12), 375 (11), 347 (21), 315 (15), 273 (11), 77 (19). 1H NMR (500 MHz, CDCl3): δ = 3.97 (s, 6H, 2OCH3), 4.03 (s, 3H, OCH3), 7.27 (t, 1H, 3JHH = 7.0 Hz, CHpara), 7.45 (t, 2H, 3JHH = 7.0 Hz, CHmeta), 8.02 (d, 2H, 3JHH = 8.0 Hz, CHortho) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 53.0, 54.0, and 54.1 (3OCH3), 108.7 (C=CS2), 120.2 (2CHortho), 126.4 (CHpara), 129.1 (2CHmeta), 135.3 (=C–CO2CH3), 135.5 (Cipso), 137.1 (=C–CO2CH3), 138.0 (C=N), 159.3 (S–C–S), 159.4 (N–C=O), 162.7 (2CO2CH3), 167.6 (CO2CH3) ppm.

Diethyl 2-(3-(methoxycarbonyl)-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5f)

Orange powder; yield: 0.25 g (54%); m.p. 165–167 ◦C. TLC RF = 0.5 (ethyl acetate/n-hexane = 4:6), IR (KBr, υ, cm−1): 1731 (CO2Et), 1491 (C=CS2), 1241 (C−O), 757 (S−C) cm−1. MS (EI): m/z (%) = 390 (M+-CO2Et, 74), 281 (42), 253 (13), 207 (100), 133 (10), 77 (14). 1H NMR (500 MHz, CDCl3): δ = 1.39 (t, 6H, 3JHH = 7.1 Hz, 2CO2CH2CH3), 4.03 (s, 3H, OCH3), 4.43 (q, 4H, 3JHH = 7.1 Hz, 2OCH2), 7.20 (t, 1H, 3JHH = 7.3 Hz, CHpara), 7.44 (t, 2H, 3JHH = 7.3 Hz, 2CHmeta), 8.01 (d, 2H, 3JHH = 8.6 Hz, 2CHortho) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 14.1 (2OCH2CH3), 53.0 (OCH3), 63.7 and 63.8 (2OCH2), 108.5 (C=CS2), 120.3 (2CHortho), 126.4 (CHpara), 129.1 (2CHmeta), 135.3 (=C–CO2CH3), 135.9 (Cipso), 137.0 (=C–CO2CH3), 138.0 (C=N), 159.1 (S–C–S), 162.3 (N–C=O), 162.7 (2CO2CH3), 167.9 (CO2CH3) ppm.

Dimethyl 2-(3-(ethoxycarbonyl)-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5 g)

Yellow powder; yield: 0.22 g (50%); m.p. 223–224 ◦C. TLC RF = 0.5 (ethyl acetate/n-hexane = 4:6), IR (KBr, υ, cm−1): 1717 (CO2Me), 1491 (C=CS2), 1227 (C−O), 759 (S−C) cm−1. MS (EI): m/z (%) = 448 (M+, 100), 347 (23), 284 (12), 257 (25), 207 (23), 77 (17). 1H NMR (500 MHz, CDCl3): δ = 1.49 (t, 3H, 3JHH = 7.1 Hz, CH3), 3.97 and 3.98 (2 s, 6H, 2OCH3), 4.51 (q, 2H, 3JHH = 7.1 Hz, CH2), 7.26 (Overlapped with solvent peak, 1H, CHpara), 7.45 (t, 2H, 3JHH = 8.6 Hz, 2CHmeta), 8.03 (d, 2H, 3JHH = 8.6 Hz, 2CHortho) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 14.4 (OCH2CH3), 54.0 and 54.1 (2OCH3), 62.4 (OCH2), 109.1 (C=CS2), 120.3 (2CHortho), 126.4 (CHpara), 129.1 (2CHmeta), 135.5 (=C–CO2CH3), 135.7 (Cipso), 137.0 (=C–CO2CH3), 138.0 (C=N), 159.4 (S–C–S), 159.5 (N–C=O), 162.4 and 162.5 (2CO2CH3 and CO2C2H5) ppm.

Diethyl 2-(3-(ethoxycarbonyl)-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5 h)

Yellow powder; yield: 0.24 g (51%); m.p. 158–159 ◦C. TLC RF = 0.65 (ethyl acetate/n-hexane = 4:6), IR (KBr, υ, cm−1): 1725 (CO2Et), 1494 (C=CS2), 1254 (C−O), 756 (S−C) cm−1. MS (EI): m/z (%) = 404 (M+-CO2Et, 58), 312 (100), 281 (18), 212 (24), 207 (45), 110 (11), 77 (7). 1H NMR (500 MHz, CDCl3): δ = 1.40 (t, 3H, 3JHH = 6.9 Hz, OCH2CH3), 1.41 (t, 3H, 3JHH = 6.9 Hz, OCH2CH3), 1.49 (t, 3H, 3JHH = 7.1 Hz, OCH2CH3), 4.40–4.45 (m, 4H, 2OCH2), 4.51 (q, 2H, 3JHH = 7.1 Hz, OCH2), 7.26 (Overlapped with solvent peak, 1H, CHpara), 7.44 (t, 2H, 3JHH = 8.2 Hz, 2CHmeta), 8.03 (d, 2H, 3JHH = 8.1 Hz, 2CHortho) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 14.1 (2OCH2CH3), 14.4 (OCH2CH3), 62.3, 63.6, and 63.7 (3OCH2), 108.6 (C=CS2), 120.3 (2CHortho), 126.3 (CHpara), 129.1 (2CHmeta), 135.7 (=C–CO2CH3), 135.9 (Cipso), 136.9 (=C–CO2CH3), 138.1 (C=N), 159.0 (S–C–S), 159.1 (N–C=O), 162.4 (2CO2C2H5), 167.8 (CO2 C2H5) ppm.

Diethyl 2-(3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)-1,3-dithiole-4,5-dicarboxylate (5i)

Orange powder; yield: 0.18 g (52%); m.p. 187–190 ◦C. TLC RF = 0.5 (ethyl acetate/n-hexane = 6:4), IR (KBr, υ, cm−1): 3462 (N–H), 1742 and 1736 (CO2Et), 1507 (C=CS2), 1287 (C−O), 767 (S−C) cm−1. MS (EI): m/z (%) = 342 (M+, 100), 297 (5), 269 (9), 242 (35), 185 (16), 140 (29), 83(16). 1H NMR (500 MHz, CDCl3): δ = 1.35–1.37 (m, 6H, 2OCH2CH3), 2.35 (s, 3H, CH3), 4.37–4.39 (m, 4H, 2OCH2CH3), 9.67 (s, 1H, NH) ppm. 13C NMR (125.59 MHz, CDCl3): δ = 14.0 and 14.1 (2OCH2CH3), 16.6 (N=C–CH3), 63.6 and 63.7 (2OCH2), 111.5 (C=CS2), 131.0 and 137.4 (2=C–CO2CH3), 144.9 (C=N), 158.6 (S–C–S), 159.2 (N–C=O), 160.6 and 165.5 (2CO2C2H5) ppm.