Efficient synthesis of novel thiadiazolo[2,3-b]quinazolin-6-ones catalyzed by diphenhydramine hydrochloride-CoCl2⋅6H2O deep eutectic solvent

In this research, a new Lewis acid-based deep eutectic solvent (LA-DES) was synthesized using diphenhydramine hydrochloride and CoCl2·6H2O, (2[HDPH]:CoCl42−), and identified by FT-IR and 1HNMR techniques. The physicochemical properties of this LA-DES, such as thermal behavior, thermal stability, and solubility in common solvents were also investigated. The catalytic ability of 2[HDPH]:CoCl42− was ascertained in the efficient synthesis of a novel array of thiadiazolo[2,3-b]quinazolin-6-one scaffolds via a one-pot three-component reaction of dimedone/1,3-cyclohexanedione, aldehydes, and 5-aryl-1,3,4-thiadiazol-2-amines/3-(5-amino-1,3,4-thiadiazol-2-yl)-2H-chromen-2-one under solvent-free conditions. This catalyst was also successfully utilized for the synthesis of mono- and bis-thiadiazolo[2,3-b]quinazolin-6-ones from dialdehydes or bis-1,3,4-thiadiazol-2-amine. The simplicity of enforcement, short reaction time, avoidance of toxic organic solvents, scalability of the synthesis procedure, excellent atom economy, high reaction mass efficiency, and low E-factor are other outstanding advantages of this newly developed method. Furthermore, due to the convenient recovery and reuse of LA-DES, this protocol is economically justified and environmentally friendly.

Green chemistry and sustainability are two crucial concepts that have gained particular attention in chemical processes 1 .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 bonds 2 .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 materials 3,4 .Compared to their previous generation, ionic liquids (ILs), DESs are more cost-efficient, relatively non-toxic, more biodegradable, and have a more straightforward preparation process [5][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 transformations [11][12][13][14][15][16] .To prepare LA-DES, the first-row transition metals can be used as Lewis acid 13,17 .Cobalt is an attractive candidate for catalysis in chemical syntheses 18 .On the other hand, the synthesis of LA-DES from CoCl 2 •6H 2 O as one of the universally used salts of cobalt can improve its catalytic activity 19 .Moreover, the high efficiency, easy recovery, and reusability of this LA-DES make this non-corrosive liquefy catalyst superior to other homogeneous liquid acid catalysts 19 .
LA-DESs have been used as the solvent [20][21][22][23][24] and/or catalyst [25][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 activities 31 .Particularly, fused thiadiazoloquinazolines are a valuable class of fused N-and S-containing heterocyclic compounds, showing outstanding anticancer 32 , antifungal 33 , antibacterial 34 , and anti-inflammatory 35 activities.Up to now, due to the significance of fused thiadiazoloquinazolines, several methods have been www.nature.com/scientificreports/developed for the synthesis of these heterocycles [36][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 chemistry 44 .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 fashions 45,46 .Due to the observance of the principles of green chemistry, MCRs have gained a special place in organic synthesis 47 .
The functional groups of the desired LA-DES were recognized by FT-IR spectroscopy (Fig. 2).In the FT-IR spectrum of CoCl 2 •6H 2 O, the broad bands at 3500 and 1598 cm −1 are related to the vibrational modes of surface water 19 .In the spectra of [HDPH]Cl 50 and [HDPH]:CoCl 4 2− , the specific bands were observed at 3029 cm −1 (sp 2 C-H) and 1111 cm −1 (C-O-C).The characteristic bands at 1454 and 1386 cm −1 are related to CH 2 and CH 3 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.
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 utilized 28 .For this purpose, the FT-IR spectra of pyridine, 2[HDPH]:CoCl

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, CoCl 2 •6H 2 O, and different LA-DESs at 120 ℃ under solvent-free conditions (Table 1, entries 2-8).Among these, 2[HDPH]:CoCl 4 2− provided the highest yield (90%) of the desired product 4a (Table 1, entry 8).Different molar ratios of [HDPH]Cl to CoCl 2 •6H 2 O 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]:CoCl 4 2− 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]:CoCl 4 2− at 120 ℃ under solvent-free conditions (Table 1, entry 8).
The structures of all the synthesized compounds were elucidated by FT-IR, 1 H NMR, and 13 C 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).
A plausible reaction mechanism for the synthesis of 4a in the presence of 2[HDPH]:CoCl .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.

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]:CoCl 4 2− 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 1 H-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.

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 factors 50,[53][54][55][56] were calculated for the www.nature.com/scientificreports/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 0.11-0.90g/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.

Table 2 .
The states of different catalysts.