Introduction

Green chemistry and sustainability are two crucial concepts that have gained particular attention in chemical processes1. In this respect, designer solvents have been introduced and developed as excellent substitutes for conventional and toxic solvents. Deep eutectic solvents (DESs) are a new generation of designer solvents, generally prepared by mixing substances capable of forming hydrogen bonds2. The formation of hydrogen bonds will be associated with charge delocalization, which causes the melting point of the DES to be lower than any of the raw materials3,4. Compared to their previous generation, ionic liquids (ILs), DESs are more cost-efficient, relatively non-toxic, more biodegradable, and have a more straightforward preparation process5,6,7,8,9,10. Among the different types of DESs, Lewis acid-based (LA-DES) and bio-based ones have been extensively used in promoting organic transformations11,12,13,14,15,16. To prepare LA-DES, the first-row transition metals can be used as Lewis acid13,17. Cobalt is an attractive candidate for catalysis in chemical syntheses18. On the other hand, the synthesis of LA-DES from CoCl2·6H2O as one of the universally used salts of cobalt can improve its catalytic activity19. Moreover, the high efficiency, easy recovery, and reusability of this LA-DES make this non-corrosive liquefy catalyst superior to other homogeneous liquid acid catalysts19.

LA-DESs have been used as the solvent20,21,22,23,24 and/or catalyst25,26,27,28,29,30 in many multicomponent reactions for the synthesis of heterocyclic compounds which is of paramount interest due to their potential pharmaceutical and biological activities31. Particularly, fused thiadiazoloquinazolines are a valuable class of fused N- and S-containing heterocyclic compounds, showing outstanding anticancer32, antifungal33, antibacterial34, and anti-inflammatory35 activities. Up to now, due to the significance of fused thiadiazoloquinazolines, several methods have been developed for the synthesis of these heterocycles36,37,38,39,40,41,42,43 However, they suffer from certain drawbacks such as multistep reaction sequences, prolonged reaction times, low yield, use of costly starting materials, corrosive reagents, and toxic solvents, as well as non-reusable catalysts which led to serious environmental and safety problems. Thus, the development of a more environmentally friendly and efficient procedure using a green and recoverable catalyst for the preparation of these worthy heterocyclic compounds is still vitally required.

Due to the synthesis of complex and structurally diverse bioactive heterocyclic compounds, multicomponent reactions (MCRs) play a paramount role in organic and medicinal chemistry44. Moreover, high convergence, facile and simple performance, pot, atom, step, and cost economy (PASCE), bond-forming-index (BFI), and minimized waste generation are unique advantages of MCRs which make them preferable to the classical stepwise fashions45,46. Due to the observance of the principles of green chemistry, MCRs have gained a special place in organic synthesis47.

As a part of our ongoing research on the synthesis of novel annulated heterocycles using green and reusable catalytic systems via multicomponent strategy48,49,50,51, we wish to describe an efficient and feasible method for the one-pot three-component synthesis of thiadiazolo[2,3-b]quinazolin-6-ones and also their mono- and bis-derivatives via the reaction of dimedone/1,3-cyclohexanedione, aldehydes/dialdehydes, and 5-substituted-1,3,4-thiadiazol-2-amines/bis-1,3,4-thiadiazol-2-amine using 2[HDPH]:CoCl42− as a novel and new LA-DES under solvent-free and green conditions (Fig. 1).

Figure 1
figure 1

Synthesis of thiadiazolo[2,3-b]quinazolin-6-one catalyzed by 2[HDPH]:CoCl42−.

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Results and discussion

Synthesis and characterization of 2[HDPH]:CoCl4 2−

As mentioned in the experimental section, the LA-DES, (2[HDPH]:CoCl42−) was easily formed by using a mixture of diphenhydramine hydrochloride and CoCl2·6H2O in a 2:1 molar ratio and identified by FT-IR, 1HNMR, DSC, and TGA/DTG techniques.

The functional groups of the desired LA-DES were recognized by FT-IR spectroscopy (Fig. 2). In the FT-IR spectrum of CoCl2·6H2O, the broad bands at 3500 and 1598 cm−1 are related to the vibrational modes of surface water19. In the spectra of [HDPH]Cl50 and [HDPH]:CoCl42−, the specific bands were observed at 3029 cm−1 (sp2 C–H) and 1111 cm−1 (C–O–C). The characteristic bands at 1454 and 1386 cm−1 are related to CH2 and CH3 stretching vibrations, respectively. Remarkably, the bands at 2400–2700 cm−1 (–N+–H) are weakened in the LA-DES spectrum, which is good evidence for the formation of hydrogen bonding.

Figure 2
figure 2

FT-IR spectra: (a) CoCl2⋅6H2O (magenta), (b) [HDPH]Cl (green), and (c) 2[HDPH]:CoCl42− (blue).

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In the 1HNMR spectrum of 2[HDPH]:CoCl42−, the aromatic hydrogens appeared as multiplet in the range of 7.42–7.31 ppm. The peaks at 4.70, 4.54, and 4.27 ppm are related to H3, H2, and H1, respectively. Surprisingly, All the mentioned peaks are down-fielded compared to the similar peaks in the [HDPH]Cl spectrum50. Also, the characteristic peak corresponding to –N+–H in 2[HDPH]:CoCl42− shifted from 12.58 to 13.21 ppm and becomes wider (Fig. 3). These observations indicate significant hydrogen bond formation in 2[HDPH]:CoCl42−.

Figure 3
figure 3

1HNMR spectra (400 MHz, CDCl3) of: (a) [HDPH]Cl (green) and (b) 2[HDPH]:CoCl42− (blue).

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Differential scanning calorimetry (DSC) was effectively used to diagnose the thermal behavior of 2[HDPH]:CoCl42−. The melting point of 2[HDPH]:CoCl42− in the DSC curve was observed at around − 2 °C (Fig. 4), which is lower than those of the raw materials (the melting points of [HDPH]Cl and CoCl2⋅6H2O are 169 °C, and 56 °C, respectively). Such a depression of melting point can be related to the formation of hydrogen bonds in 2[HDPH]:CoCl42− deep eutectic mixture.

Figure 4
figure 4

DSC curve of 2[HDPH]:CoCl42−.

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To examine the thermal stability of the 2[HDPH]:CoCl42−, TGA analysis was employed. According to Fig. 5, the new LA-DES has good thermal stability up to about 329 °C; weight losses of only 5% at 136.1 °C and 10% at 232.9 °C were observed. The residual weight at 500 ℃ is 15.90%, which matches well with the theoretical CoCl2 weight % (15.80%).

Figure 5
figure 5

Thermogravimetric analysis and derivative thermogravimetry (TGA/DTG) of 2[HDPH]:CoCl42−.

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Acidity is one of the most important physical properties of DESs, making them applicable for industrial usage. To determine the acidity of DES, FT-IR spectroscopy and pyridine as a probe are commonly utilized28. For this purpose, the FT-IR spectra of pyridine, 2[HDPH]:CoCl42− and pyridine-2[HDPH]:CoCl42− were investigated52. In the FT-IR spectrum of pyridine-2[HDPH]:CoCl42− (Fig. 6a), the characteristic band at 1446 cm−1, indicates that 2[HDPH]:CoCl42− has Lewis acidic sites which interact with pyridine groups. Also, the band appeared at 1635 cm−1 in the FT-IR spectrum of pyridine-2[HDPH]:CoCl42− could be attributed to the formation of pyridinium ions ([PyH]+) upon the interaction of pyridine with Brønsted acid sites of the LA-DES3,50. Such an interaction has been displayed in Fig. 6b. To confirm the acidity, pH of the solutions of CoCl2⋅6H2O (4 × 10−3 mol L−1), [HDPH]Cl (8 × 10–3 mol L−1), and 2[HDPH]:CoCl42− (8 × 10–3 mol L−1) were measured and found to be 5.17, 5.39, and 4.77, respectively. Consequently, 2[HDPH]:CoCl42− can be applied as an efficient acidic catalyst for useful organic transformations.

Figure 6
figure 6

FT-IR spectra: (a) Pyridine (red), 2[HDPH]:CoCl42− (blue), and 2[HDPH]:CoCl42− in pyridine (green). (b) The interaction between the Lewis and Brønsted acid sites of the catalyst with pyridine.

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Optimization of the reaction conditions

For the initial investigation, the reaction between 4-methylbenzaldehyde, 5-phenyl-1,3,4-thiadiazol-2-amine, and dimedone was selected as a model to optimize the reaction conditions. In the absence of the catalyst, the desired three-component product 4a was obtained with only 5% yield even after 4 h at 120 ℃ under solvent-free conditions (Table 1, entry 1). Then, the titled reaction was performed in the presence of 0.2 mmol of catalysts including [HDPH]Cl, CoCl2·6H2O, and different LA-DESs at 120 ℃ under solvent-free conditions (Table 1, entries 2–8). Among these, 2[HDPH]:CoCl42− provided the highest yield (90%) of the desired product 4a (Table 1, entry 8). Different molar ratios of [HDPH]Cl to CoCl2·6H2O were examined (Table 1, entries 8–10); 2:1 molar ratio was found to be more suitable for this transformation (Table 1, entry 8). It is noteworthy that increasing the loading of 2[HDPH]:CoCl42− to 0.3 mmol did not improve the product yield, but decreasing the loading of the catalyst to 0.1 mmol led to a lower yield of the product (Table 1, entries 11, 12). In addition, the reaction was also tested at various temperatures (Table 1, entries 8, 13–15), and 120 ℃ was discovered to be more suitable for this transformation. Consequently, the optimum reaction conditions for the synthesis of target product 4a were attained by using 0.2 mmol of 2[HDPH]:CoCl42− at 120 ℃ under solvent-free conditions (Table 1, entry 8).

Table 1 Optimization of the reaction conditions for the model reaction.
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Synthesis of thiadiazolo[2,3-b]quinazolin-6-one derivatives

The applicability and scope of this protocol to the synthesis of thiadiazolo[2,3-b]quinazolin-6-one derivatives were then checked under optimal conditions. As shown in Fig. 7, the three-component reaction between dimedone/1,3-cyclohexanedione, 5-aryl-1,3,4-thiadiazol-2-amines and aromatic aldehydes with electron-donating and electron-withdrawing groups at various positions of aromatic ring proceeded smoothly in the presence of 2[HDPH]:CoCl42− at 120 ℃ under solvent-free conditions which afforded the corresponding thiadiazolo[2,3-b]quinazolin-6-ones 4a–4s in 73–96% yields. Under the same reaction conditions, 6-chloro-4-oxo-4H-chromene-3-carbaldehyde as a heterocyclic aldehyde and 3-phenyl propanal, as an aliphatic aldehyde gave the desired products 4t, 4u, and 4v in 85%, 86%, and 75% yields, respectively.

Figure 7
figure 7

Synthesis of thiadiazolo[2,3-b]quinazolin-6-ones catalyzed by 2[HDPH]:CoCl42−.

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It is also interesting to note that a scale-up synthesis of 4a was carried out under these conditions. On a 5 mmol scale, dimedone reacted with 4-methylbenzaldehyde and 5-phenyl-1,3,4-thiadiazol-2-amine in the presence of 2[HDPH]:CoCl42− at 120 ℃ under solvent-free conditions to afford the corresponding thiadiazolo[2,3-b]quinazolin-6-ones 4a in 88% yields.

To further demonstrate the efficacy of the present method, the synthesis of thiadiazolo[2,3-b]quinazolin-6-one derivatives was performed under optimal conditions using 3-(5-amino-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one in place of 5-aryl-1,3,4-thiadiazol-2-amine and the corresponding products 6a–6d were obtained in 71–85% yields (Fig. 8).

Figure 8
figure 8

Synthesis of thiadiazolo[2,3-b]quinazolin-6-ones from 3-(5-amino-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one catalyzed by 2[HDPH]:CoCl42−.

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To spotlight the attractive performance of this catalytic system, mono- and bis-thiadiazolo[2,3-b]quinazolin-6-one scaffolds were prepared from different dialdehydes. As it is evident from Fig. 9, when dimedone/1,3-cyclohexanedione (1 mmol) reacted with 5-aryl-1,3,4-thiadiazol-2-amines (1 mmol) and dialdehydes (1 mmol) under the optimized conditions, the desired mono-thiadiazolo[2,3-b]quinazolin-6-one scaffolds were selectively produced in 65–75% yields. Also, the corresponding bis-thiadiazolo[2,3-b]quinazolin-6-ones were achieved in 60–65% yields by using 2 mmol dimedone/1,3-cyclohexanedione, 2 mmol 5-aryl-1,3,4-thiadiazol-2-amines, and 1 mmol dialdehydes under the same conditions.

Figure 9
figure 9

Synthesis of mono- and bis-thiadiazolo[2,3-b]quinazolin-6-ones from dialdehydes catalyzed by 2[HDPH]:CoCl42−.

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To reveal further utility of the current method, mono- and bis-thiadiazolo[2,3-b]quinazolin-6-ones were synthesized under optimal conditions using bis-1,3,4-thiadiazol-2-amine in place of dialdehyde. As observed in Fig. 10, the reaction of dimedone with aryl aldehyde and 5,5′-(butane-1,4-diylbis(sulfanediyl))bis(1,3,4-thiadiazol-2-amine) in 1:1:1 and 2:2:1 molar ratios in the presence of 2[HDPH]:CoCl42− at 120 ℃ under solvent-free conditions proceeded efficiently to generate the corresponding mono- and bis-thiadiazolo[2,3-b]quinazolin-6-ones in 60–76% and 57–70% yields, respectively. Finally, it should be stressed that all the above-mentioned findings reveal the brilliant eligibility and applicability of this catalytic system in the synthesis of these vital fused heterocyclic compounds.

Figure 10
figure 10

Synthesis of mono- and bis-thiadiazolo[2,3-b]quinazolin-6-ones from bis-1,3,4-thiadiazol-2-amine catalyzed by 2[HDPH]:CoCl42−.

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The structures of all the synthesized compounds were elucidated by FT-IR, 1H NMR, and 13C NMR spectra as well as elemental analysis. Furthermore, the structure of 4s was confirmed by single crystal X-ray analysis (Fig. 11; CCDC 2297765, Tables S1 and S2).

Figure 11
figure 11

X-ray crystallographic structure of 4s.

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A plausible reaction mechanism for the synthesis of 4a in the presence of 2[HDPH]:CoCl42− is illustrated in Fig. 12. Initially, Knoevenagel condensation between the enol form of dimedone 1 and aldehyde 2 activated by the catalyst gives intermediate Ӏ. Then, LA-DES catalyzed Michael addition of 5-aryl-1,3,4-thiadiazol-2-amine 3 to intermediate Ӏ resulting in the formation of intermediate II, which is transformed to intermediate IIӀ after keto-enol tautomerism. Next, intermediate ӀV is formed by the cyclization of intermediate IIӀ in the presence of 2[HDPH]:CoCl42−. Finally, the elimination of water from intermediate ӀV affords the final product 4a, regenerating LA-DES, which can be used for the next catalytic cycle.

Figure 12
figure 12

Proposed mechanism for the synthesis of 4a.

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Catalyst recycling and reuse

Due to the atom economy, easy preparation, recovery, and reuse of DESs, they are considered green and sustainable solvents and catalysts in organic reactions. In this regard, the recyclability of the 2[HDPH]:CoCl42− was checked in the model reaction. After the consumption of precursors, the mixture was cooled to room temperature, water was added, and stirred to dissolve LA-DES. The resulting precipitate was collected by simple filtration followed by washing with water. The filtrate was evaporated at 80 °C under vacuum and the recovered LA-DES was reused for the subsequent cycle. As can be seen in Fig. 13a, the catalyst is reusable for up to six cycles without noticeable loss in its activity. Comparison of the FT-IR (Fig. 13b) and 1H-NMR spectra (Fig. 14) of the fresh and recovered LA-DES shows that the catalyst is stable during the reaction which is very important from the practical point of view.

Figure 13
figure 13

(a) Recovery and reuse of the catalyst for the synthesis of 4a. (b) FT-IR spectra of fresh (blue) and reused (pink) of 2[HDPH]:CoCl42−.

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Figure 14
figure 14

1H-NMR spectra of fresh (blue) and reused (pink) of 2[HDPH]:CoCl42−.

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Green chemistry metric evaluation

To introduce the existing method as an eco-friendly and green synthetic path for the preparation of thiadiazolo[2,3-b]quinazolin-6-one scaffolds, a number of green metric factors50,53,54,55,56 were calculated for the synthesized compounds (Figs. 15 and 16). In this respect, effective mass yield (EMY), and reaction mass efficiency (RME) for all the synthesized compounds were calculated and found to be in the range of 52.74–89.69%. To show the eco-compatibility and the atom economy of the present protocol, the E-factor, and atom economy (AE) were also determined which were found to be in ranges of 0.11–0.90 g/g and 90.27–96.18%, respectively. Due to the elimination of only water molecules in the present method, excellent results were obtained for the E-factor and atom economy. Also, the calculated atom efficiency (AEf), optimum efficiency (OE), and carbon efficiency (CE) for this procedure were up to 89.64%, 96.06%, and 96%, respectively. The obtained data together with the recoverability of the catalyst and solvent-free conditions introduce this protocol as a green and environmentally benign pathway for the preparation of thiadiazolo[2,3-b]quinazolin-6-ones. The detailed calculations are presented in the Supporting Information.

Figure 15
figure 15

Schematic diagram of calculated green metrics values, AEf, OE, and EMY for the synthesized compounds (4a-12c).

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Figure 16
figure 16

Radar plot of evaluated green chemistry metrics for compounds (4a-12c).

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Experimental

General information

The chemicals were purchased from Fluka and Merck chemical companies. 5-aryl-1,3,4-thiadiazol-2-amines, 3-(5-amino-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one, 5,5′-(butane-1,4-diylbis(sulfanediyl))bis(1,3,4-thiadiazol-2-amine) and 2,2′-(butane-1,4-diylbis(oxy))dibenzaldehyde were prepared similar to the reported methods57,58,59,60. Melting points were determined using a Stuart Scientific SMP2 apparatus. FT-IR spectra were recorded on a Nicolet-Impact 400D spectrophotometer. 1H and 13C NMR (400 and 100 MHz) spectra were recorded on a Bruker Avance 400 MHz spectrometer using CDCl3 solvent. Elemental analysis was performed on a LECO, CHNS-932 analyzer. Thermogravimetric and derivative thermogravimetric analysis (TGA/DTG) was carried out on a Perkin-Elmer STA 6000 instrument under nitrogen flow at a uniform heating rate of 10 ℃ min−1 in the range of 30–600 ℃. Differential scanning calorimetry (DSC) was carried out with a TA Instrument Model DSC13-setaram under a nitrogen atmosphere with a scan rate of 10 ℃ min−1 in the range − 60 to 20 ℃.

General procedure for the synthesis of Lewis acid-based deep eutectic solvents (LA-DESs)

Diphenhydramine hydrochloride was mixed with the metal chloride hydrate at the specified molar ratio (Table 2) and heated up to 90 ℃ with mild stirring until it turned into a transparent liquid. The synthesized LA-DES, after cooling, was utilized without any further purification.

Table 2 The states of different catalysts.
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Synthesis of thiadiazolo[2,3-b]quinazolin-6-ones catalyzed by 2[HDPH]:CoCl4 2−

In a screw-cap glass tube with a magnetic stirrer, a mixture of dimedone/1,3-cyclohexanedione 1 (1 mmol), aldehyde 2 (1 mmol), 5-substituted-1,3,4-thiadiazol-2-amine 3 or 5 (1 mmol) and 2[HDPH]:CoCl42− (0.2 mmol) was heated at 120 ℃ under solvent-free conditions for the appropriate time mentioned in Figs. 7 and 8. Upon consumption of the precursors as depicted by TLC (eluent: n-hexane/EtOAc, 2:1), the reaction mixture was allowed to cool to room temperature. To dissolve 2[HDPH]:CoCl42−, water (5 mL) was added, and the resulting solid crude product was separated by simple filtration, washed with water (5 mL), dried, and crystallized from ethyl acetate to afford the pure product. In some cases, chromatography on silica gel (eluent: n-hexane/EtOAc, 2:1) is required to obtain the pure product.

Synthesis of mono and bis-thiadiazolo[2,3-b]quinazolin-6-ones from dialdehyde catalyzed by 2[HDPH]:CoCl4 2−

In a screw-cap glass tube with a magnetic stirrer, a mixture of dimedone/1,3-cyclohexanedione 1 (1 mmol), dialdehyde 7 (1 mmol), 5-aryl-1,3,4-thiadiazol-2-amine 3 (1 mmol) and 2[HDPH]:CoCl42− (0.2 mmol) was heated at 120 ℃ under solvent-free conditions for the specified time demonstrated in Fig. 9. After completion of the reaction (monitored by TLC; eluent: n-hexane/EtOAc, 2:1), the workup was carried out according to the procedure used for thiadiazolo[2,3-b]quinazolin-6-ones to afford the pure mono-derivatives 8a–8d in 70–75% yields. For the synthesis of bis-thiadiazolo[2,3-b]quinazolin-6-ones, dimedone/1,3-cyclohexanedione 1 (1 mmol) reacted with dialdehyde 7 (0.5 mmol) and 5-aryl-1,3,4-thiadiazol-2-amine 3 (1 mmol) in the presence of LA-DES (0.2 mmol) and the mixture was heated at 120 ℃ under solvent-free conditions. The reaction progress was checked by TLC (eluent: n-hexane/EtOAc, 2:1). The workup and purification were performed according to the above-mentioned procedure to furnish the desired products 9a-9d in 60–65% yields (Fig. 9).

Synthesis of mono and bis-thiadiazolo[2,3-b]quinazolin-6-ones from bis-1,3,4-thiadiazol-2-amine catalyzed by 2[HDPH]:CoCl4 2−

In a screw-cap glass tube with a magnetic stirrer, dimedone 1 (1 mmol), aldehyde 2 (1 mmol), and 5,5′-(butane-1,4-diylbis(sulfanediyl))bis(1,3,4-thiadiazol-2-amine) 10 (1 mmol) were added to 2[HDPH]:CoCl42− (0.2 mmol) and the mixture was heated at 120 ℃ under solvent-free conditions for the specified time indicated in Fig. 10. On completion of the reaction (monitored by TLC analysis; eluent: n-hexane/EtOAc, 2:1), the workup was carried out according to the procedure for the preparation of thiadiazolo[2,3-b]quinazolin-6-one and the desired pure product 11a–11c were obtained in 60–76% yields. All the steps for the synthesis of bis-thiadiazolo[2,3-b]quinazolin-6-ones (12a–12c, 57–70%) from bis-1,3,4-thiadiazol-2-amine and their purification were the same as those of mono-thiadiazolo[2,3-b]quinazolin-6-ones except that 0.5 mmol of 5,5′-(butane-1,4-diylbis(sulfanediyl))bis(1,3,4-thiadiazol-2-amine) reacted with 1 mmol of each dimedone 1 and aldehyde 2 (Fig. 10).

Conclusions

In summary, an efficient, convenient, green, and straightforward protocol has been developed for the preparation of a series of thiadiazolo[2,3-b]quinazolin-6-ones via a one-pot, single-step, multicomponent reaction of dimedone/1,3-cyclohexanone, aldehydes, and 5-aryl-1,3,4-thiadiazol-2-amines/3-(5-amino-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one) in the presence of 2[HDPH]:CoCl42− as an LA-DES under solvent-free conditions. This effective process is also applicable to the synthesis of mono- and bis-thiadiazolo[2,3-b]quinazolin-6-ones from dialdehydes or bis-1,3,4-thiadiazol-2-amine. High to excellent yields, high reaction rates, avoiding toxic organic solvents, operational simplicity, easy separation and recyclability of the catalyst, large-scale synthetic applicability, formation of water as green waste, excellent atom economy, high reaction mass efficiency, and low E-factor are outstanding features of this protocol.