An efficient one-pot synthesis of 2,5-disubstituted-1,3,4-thiadiazoles from aldehydes and hydrazides using Lawesson’s reagent

Five-membered heterocyclic-ring systems, such as thiadiazoles, remain an important and prevalent scaffold in the development of novel leads in medicinal chemistry for a variety of therapeutic targets. A two-step, one-pot synthesis of 2,5-disubstituted-1,3,4-thiadiazole derivatives from aryl hydrazides and aryl aldehydes using Lawesson’s reagent is described, yielding 2,5-disubstituted-1,3,4-thiadiazoles in moderate-to-high yields. Based on preliminary biological experiments, some of the newly synthesized thiadiazoles show antioxidant activity


Introduction
Heterocyclic compounds are defined, according to IUPAC (International Union of Pure and Applied Chemistry), as cyclic compounds including at least two different atoms such as oxygen, sulfur or nitrogen in the ring.These compounds are important due to their wide range of biological activities.For example, the antiviral Sovaldi (Gilead Sciences), the antipsychotic Abilify (Otsuka), and the anti-inflammatory Nexium are among the most popular and widely used drugs worldwide. 1mong the heterocyclic compounds, 1,3,4-thiadiazole has attracted special interest in recent years in various areas, including pharmaceutical, agricultural, and materials chemistries.1,3,4-Thiadiazole is a weak base due to the inductive effect of the sulfur in the ring, and possesses a relatively high aromaticity. 2,3,4In addition, the ring is electron deficient due to the electron-withdrawing effects of the nitrogen atoms. 2 For these reasons, In the pharmaceutical field, 1,3,4-thiadiazole derivatives are known to exhibit diverse biological activities, such as antimicrobial 5 , antiviral 6 , anticonvulsant 7 , antifungal, [8][9][10] antitubercular, [11][12][13] anticancer, 14 and immunomodulatory 15 activities.Some examples of commercially-available drugs containing the 1,3,4thiadiazole ring are Megazol, Acetazolamide (Diamox), Furidiazine, and Desaglybuzole, shown in Figure 1. 16,17gure 1.Commercially available 1,3,4-thiadiazole drugs Synthetic methods to produce 1,3,4-thiadiazoles have been developed and studied over many decades due to the interest following the discovery of their diverse pharmacological and physiological activities.Wellknown synthetic methods for 1,3,4-thiadiazoles include starting materials such as N,N'-diacylhydrazines, 18,19 thiosemicarbazides 20 or thiohydrazides, 21,22 as well as the transformation of 1,3,4-oxadiazoles. 23Most existing synthetic methods, however, require harsh conditions, multi-step procedures, and scarce starting materials or experience difficulty in forming non-symmetric 1,3,4-thiadiazoles.Therefore, it is still necessary to develop a more efficient synthetic method to produce 1,3,4-thiadiazoles.We, herein, report a highly efficient, two-step, one-pot synthetic method for 2,5-disubstituted-1,3,4-thiadiazoles from aldehydes and hydrazides in good-toexcellent yields using a sequence of N-aroylhydrazone formation, thionation, cyclization and oxidation.
After refluxing for 2 hr, the ethanol was evaporated in vacuo.To a remaining crude 3a, LR and solvent were added, followed by addition of a base.The resulting mixture was refluxed for 10 hr.b Isolated yield.c Two-pot synthesis including separation of 3a.
Based on the previous experimental results and the literature, 27 the mechanism of this reaction can be proposed as shown in Scheme 3. Following formation of the N-aroylhydrazone intermediate (3), it would react with LR to give the thiohydrazone (4).It is believed that dihydrothiadiazole (4'), which is the preferred tautomeric form of the thiohydrazone (4), is readily oxidized to produce the disubstituted-1,3,4-thiadiazole (5).Scheme 3. Proposed mechanism for formation of the 1,3,4-thiadiazoles.
To clarify the mechanism of this reaction, we needed to prove formation of intermediate 4 and/or 4'.8][29] After the reaction of the phenyl thiohydrazide (9) with benzaldehyde (2a), the ring tautomer dihydrothiadiazole (4') was obtained, rather than the thiohydrazone (4) (Scheme 4).This was confirmed by analyzing 1 H and 13 C NMR spectra compared with the spectral data from a previous study. 29During our one-pot reaction, a TLC spot of dihydrothiadiazole (4') was also observed below the spot of 2,5-diphenyl-1,3,4-thiadiazole (5a).In addition, a small amount of 4' was isolated and its structure confirmed.As a result, it is suggested that the dihydrothiadiazole intermediate (4') is directly formed from 3, and immediately oxidized under the reaction conditions to produce 2,5-diphenyl-1,3,4-thiadiazole (5a).

Scheme 4. Results of literature method for synthesis of intermediates 4 and/or 4'
As mentioned above, the use of a base is, presumably, to inhibit the reverse reaction of N-acylhydrazones (3) to aldehydes (2) and hydrazides (1), and, thereby, improve the overall yield of the reaction.Also, according to the literature, pyridine has been reported to stabilize and activate the phosphine ylide by forming stable complexes with P4S10 30 and Woollins reagents (WR), 31 which has a structure similar to LR. LR is known to be in equilibrium with its dithiophosphine ylide in solution (Figure 2).This ylide is said to be the reactive intermediate in the thionation processes with LR. [24][25][26] Therefore, we hypothesized that DMAP would protect the inverse-hydrolysis reaction of N-acylhydrazone (3), stabilize and activate LR by forming a stable DMAPdithiophosphine complex like pyridine.To extend the one-pot synthetic method to various 1,3,4-thiadiazoles (5), different combinations of aroylhydrazides (1a-n) and benzaldehydes (2a-n) were reacted under the same conditions as 5a.First, the same amounts of aldehyde and hydrazide were reacted in refluxing ethanol for two hours.After the ethanol was evaporated, the remaining crude thiahydrazone (3) in the reaction vessel was reacted in toluene, refluxing with 0.8 equivalent of LR and 1.2 equivalents of DMAP for 12 hours as shown in Scheme 5. Scheme 5. Synthesis of 2,5-diphenyl-1,3,4-thiadiazole derivatives (5).Note: Benzaldehyde (1.0 mmol) and benzoylhydrazide (1.0 mmol) were refluxed in ethanol for 2 hr, evaporated in vacuo, and then reacted with LR and DMAP in refluxing toluene.
A series of 2,5-disubstituted-1,3,4-thiadiazoles (5a-m) were prepared in moderate-to-high yields (75% to 97%) from hydrazides (1a-n) and aldehydes (2a-n), the results of which are summarized in Table 2.In summary, a two-step, one-pot reaction was accomplished in refluxing ethanol using the same amounts of hydrazide 1 and aldehyde 2 without separating the hydrazine intermediate 3, and in the absence of added oxidant.

Conclusions
In conclusion, we have developed a highly efficient, two-step, one-pot synthesis of 2,5-disubstituted-1,3,4thiadiazoles in moderate-to-high yields from benzaldehydes and hydrazines using LR in the absence of an additional oxidant.Based on the confirmation of the formation of thiadiazoline intermediate, a reaction mechanism has been proposed and the role of the base additives in this reaction has been suggested.According to preliminary biological experiments, some of the newly synthesized thiadiazoles show antioxidant activity.These results will be presented in a future study.

Experimental Section
General.
Melting points were determined using a Barnstead Electrothermal 9100 melting point apparatus. 1H NMR and 13 C NMR spectra were recorded on a JEOL 300 MHz spectrometer and JEOL 75MHz spectrometer, respectively.Chemical shifts (δ) are reported in parts per million (ppm) and coupling constants (J) in Hertz (Hz).The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br s = broad singlet.High resolution mass spectrometry (HRMS) was performed using a JEOL JMS-700 M station mass spectrometer and electron impact ionization (EI-magnetic sector) mass spectrometer.
2,5-Diphenyl-1,3,4-thiadiazole (5a) 32,33  Procedure for synthesis of compound 9 28 Compound 8 (2.0 g, 9.4 mmol) was dissolved in 1 M NaOH (10 mL, 1 eq) and H2O (10 ml).Upon addition of hydrazine hydrate (1.7 g, 55%, 18.8 mmol), the orange color disappeared.After consumption of the starting material, the reaction mixture was acidified to pH 5-6 with dilute HCl (aq) and stirred for 1 hr while cooling in an ice bath.A white solid was filtered and recrystallized from water to produce benzothiohydrazide (9) as white crystals.Benzothiohydrazide (9)   29 In a round-bottom flask, benzaldehyde (0.5 mmol) and 9 (0.5 mmol) were added in ethanol (5 ml) for 2 hr at room temperature.After the reaction was complete, the ethanol was evaporated under vacuum, and the product was obtained by recrystallization in a mixture of ethyl acetate and hexane.