New Route Synthesis of Thiadiazoles, Bisthiadiazoles, Thiadiazolotriazines, and Pyrazolothiadiazoles Based on Hydrazonoyl Halides and Dihydrazinylthiadiazole

Synthesis and characterization of new thiadiazoles, bisthiadiazoles from the reaction of mono- and di-hydrazonoyl halides with various hydrazinecarbodithioate derivatives were studied. Treatment of hydrazonoyl halides with 2,5-dihydrazinyl-1,3,4-thiadiazole afforded new bistriazines containing thiadiazole; we also examined the reaction of 2,5-dihydrazinyl-1,3,4-thiadiazole with active methylene compounds to afford new pyrazoles containing thiadiazole compounds. The new synthesized compounds were identified by elemental analysis and various spectral data (Fourier transform infrared spectroscopy, mass spectrometry, 1H and 13C nuclear magnetic resonance).


Introduction
Hydrazonoyl halides are useful for the synthesis of assorted and various heterocyclic derivatives [1][2][3][4]. Treatment of hydrazonoyl halides with dithioate derivatives in dioxane and in the presence of base gave the thiadiazole derivatives [5]. Thiadiazoles are heterocyclic organic compounds with a comprehensive range of biological activities, such as anticancer [6], antivirus [7], antimicrobial [8], and anti-inflammatory [9]. Heterocycles are used in analytical chemistry [10] and have pharmaceutical properties [11]. Thiadiazoles are described and quantum chemistry is used to elucidate the chemical reactions in [12]. Studying the aromaticity of thiadiazoles via various quantitative methods is reported in [13,14].
Ferrocene is used as a multi-nuclear substance possessing the properties of both organometlallic and coordination complexes.

Results and Discussion
This work is a continuation of our active research in the area of hydrazonoyl halides and their reactions with different moieties, reported in [2,3]. These principles were extended in the present paper. Thus, hydrazonoyl halide 1 [24] was reacted with methyl hydrazinecarbodithioate 2 [25] in ethanol and in the presence of triethylamine under heating until complete elimination of methanethiol. The reaction mixture gave a single isolated product in each case 5a-e monitored by thin layer chromatography (TLC). The formation of the final products can be explained by stepwise mechanism involving nucleophilic substitution reaction to give acyclic thiohydrazonate ester 3, which undergoes intramolecular cyclization to yield the spirothiadiazole intermediate 4, which was followed by elimination of methanethiol in order to give the final products 5a-e or via 1,3-dipolar cycloaddition of nitrilimine (generated in situ from hydrazonoyl halides in the presence of triethylamine) to C=S of 2, which was followed by elimination of methanethiol to give the final products 5a-e. The final products were elucidated on the basis of spectral data and elemental analysis as depicted in Scheme 1. The infrared (IR) spectrum of 5a-e showed absorption bands for NH 2 group around 3333-3220 cm −1 . In addition, the 1 H-NMR spectrum for 5 showed signals attributed to the NH 2 protons 5.72-5.70 ppm, as depicted in Scheme 1.

Results and Discussion
This work is a continuation of our active research in the area of hydrazonoyl halides and their reactions with different moieties, reported in [2,3]. These principles were extended in the present paper. Thus, hydrazonoyl halide 1 [24] was reacted with methyl hydrazinecarbodithioate 2 [25] in ethanol and in the presence of triethylamine under heating until complete elimination of methanethiol. The reaction mixture gave a single isolated product in each case 5a-e monitored by thin layer chromatography (TLC). The formation of the final products can be explained by stepwise mechanism involving nucleophilic substitution reaction to give acyclic thiohydrazonate ester 3, which undergoes intramolecular cyclization to yield the spirothiadiazole intermediate 4, which was followed by elimination of methanethiol in order to give the final products 5a-e or via 1,3-dipolar cycloaddition of nitrilimine (generated in situ from hydrazonoyl halides in the presence of triethylamine) to C=S of 2, which was followed by elimination of methanethiol to give the final products 5a-e. The final products were elucidated on the basis of spectral data and elemental analysis as depicted in Scheme 1. The infrared (IR) spectrum of 5a-e showed absorption bands for NH2 group around 3333-3220 cm −1 . In addition, the 1 H-NMR spectrum for 5 showed signals attributed to the NH2 protons 5.72-5.70 ppm, as depicted in Scheme 1.
Analogously, novel compounds 11 and 12 were prepared via nucleophilic substitution reaction of 1,4-diphenylterephthalohydrazonoyl dichloride 9 [27] with methyl 2-(1-ferrocenylethylidene) hydrazinecarbodithioate 8 or methyl 2-(1-phenylethylidene)hydrazinecarbodithioate 10 [28] in EtOH/DMF and in the presence of triethylamine acting as base to give the final products 11 and 12 in good yields, as depicted in Scheme 2. The final products 11 and 12 gave a satisfactory elemental analysis and spectroscopic data (IR, NMR, and MS) consistent with their assigned structures (Scheme 2). The IR spectra of products 11 and 12 indicate the absence of NH at 3300 cm −1 (NH). Pleasingly, reaction of 2,5-dihydrazinyl-1,3,4-thiadiazole 13 [29] with hydrazonoyl bromide 14 [30] in dioxane in the presence of trimethylamine as a base under reflux conditions proceeded smoothly to afford 17; it is suggested that the reaction starts with the formation of hydrazide 15 followed by cyclization to give the product 17 via elimination of water molecule as depicted in Scheme 3. The compounds were characterized by elemental analysis and spectral data (IR, MS, 1 H-NMR spectra) . Pleasingly, reaction of 2,5-dihydrazinyl-1,3,4-thiadiazole 13 [29] with hydrazonoyl bromide 14 [30] in dioxane in the presence of trimethylamine as a base under reflux conditions proceeded smoothly to afford 17; it is suggested that the reaction starts with the formation of hydrazide 15 followed by cyclization to give the product 17 via elimination of water molecule as depicted in Scheme 3. The compounds were characterized by elemental analysis and spectral data (IR, MS, 1 H-NMR spectra). Analogously, novel compounds 11 and 12 were prepared via nucleophilic substitution reaction of 1,4-diphenylterephthalohydrazonoyl dichloride 9 [27] with methyl 2-(1-ferrocenylethylidene) hydrazinecarbodithioate 8 or methyl 2-(1-phenylethylidene)hydrazinecarbodithioate 10 [28] in EtOH/DMF and in the presence of triethylamine acting as base to give the final products 11 and 12 in good yields, as depicted in Scheme 2. The final products 11 and 12 gave a satisfactory elemental analysis and spectroscopic data (IR, NMR, and MS) consistent with their assigned structures (Scheme 2). The IR spectra of products 11 and 12 indicate the absence of NH at 3300 cm −1 (NH). Pleasingly, reaction of 2,5-dihydrazinyl-1,3,4-thiadiazole 13 [29] with hydrazonoyl bromide 14 [30] in dioxane in the presence of trimethylamine as a base under reflux conditions proceeded smoothly to afford 17; it is suggested that the reaction starts with the formation of hydrazide 15 followed by cyclization to give the product 17 via elimination of water molecule as depicted in Scheme 3. The compounds were characterized by elemental analysis and spectral data (IR, MS, 1 H-NMR spectra) .

Experimental Section
All melting points were determined on an electrothermal apparatus and are uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer (Shimadzu, Tokyo, Japan). 1 H-NMR spectra were recorded in CDCl3 and (CD3)2SO solutions on a Varian Gemini 300 MHz spectrometer (Agilent, Palo Alto, CA, USA), and chemical shifts are expressed in δ units using tetramethylsilane (TMS) as an internal reference. Mass spectra were recorded on a Shimadzu GC-MS QP 1000 EX instrument. Elemental analyses were carried out at the Microanalytical Canter of Cairo University.

Synthesis of Thiadiazoles (5a-e)
To a solution of hydrazonoyl bromides 1a-e (5 mmol) and methyl hydrazinecarbodithioate 2 (0.61 g, 5 mmol) in ethanol (40 mL) was added triethylamine (TEA) (5 mmol, 0.7 mL), and the mixture was refluxed for 3 h monitored by TLC. The resulting solids were collected and recrystallized from an appropriate solvent to give final products 5a-e.

Experimental Section
All melting points were determined on an electrothermal apparatus and are uncorrected. IR spectra were recorded (KBr discs) on a Shimadzu FT-IR 8201 PC spectrophotometer (Shimadzu, Tokyo, Japan). 1 H-NMR spectra were recorded in CDCl 3 and (CD 3 ) 2 SO solutions on a Varian Gemini 300 MHz spectrometer (Agilent, Palo Alto, CA, USA), and chemical shifts are expressed in δ units using tetramethylsilane (TMS) as an internal reference. Mass spectra were recorded on a Shimadzu GC-MS QP 1000 EX instrument. Elemental analyses were carried out at the Microanalytical Canter of Cairo University.

Synthesis of Thiadiazoles (5a-e)
To a solution of hydrazonoyl bromides 1a-e (5 mmol) and methyl hydrazinecarbodithioate 2 (0.61 g, 5 mmol) in ethanol (40 mL) was added triethylamine (TEA) (5 mmol, 0.7 mL), and the mixture was refluxed for 3 h monitored by TLC. The resulting solids were collected and recrystallized from an appropriate solvent to give final products 5a-e. Method A: An equimolar amount of the appropriate hydrazonoyl bromides 1a (5 mmol, 1.135 g) and methyl 2-(1-ferrocenylethylidene)hydrazinecarbodithioate 8 (5 mmol, 1.645 g) in 10 mL DMF, 30 mL ethanol, triethylamine (5 mmol, 0.7 mL); the reaction mixtures were refluxed for 7 h at boiling point monitored by TLC. The solvent was evaporated, and the residue was triturated with methanol. The formed solid was filtered and recrystallized from appropriate to give compounds 7.

Conclusions
In conclusion, the studied reactions provide a facile new route for synthesized thiadiazoles, bisthiadiazoles, pyrazolothiadiazoles, and thiadiazolotriazines via the utility of hydrazonoyl halides and 2,5-dihydrazinyl-1,3,4-thiadiazole. The final products were identified by different techniques, such as elemental analysis and FT-IR, NMR, mass spectrometry, and alternate synthesis whenever possible.