Synthesis and Reactions of Novel 2,5-Disubstituted 1,3,4-Thiadiazoles

Abstract The desired 1,3,4-thiadiazole compounds bearing different substituents were obtained by the cyclization of the corresponding thiosemicarbazide followed by the reaction with electrophilic reagents, such as aromatic aldehydes, isatin, phenyl isothiocyanate, and carbon disulfide. The newly synthesized 2,5-disubstituted 1,3,4-thiadiazoles were obtained in good yields and their structures were elucidated by spectral data and elemental analysis. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT

The insoluble fraction in toluene was separated and detected as the acetylated product 4, whose structure was investigated and confirmed using the analytical and spectroscopic data. Thus, the IR spectrum of compound 4 show the stretching Scheme 2. Cyclization of 2 using AcOH. absorption band for carbonyl group of ester at 1725 cm -1 . The electron ionizationmass spectrometry (EI-MS) spectrum of 4 displayed the radical cation peak at m/z = 384 (M + 2, 4.9%) and the cation R-C≡O + at m/z = 183 (46.7%).
The formation of compound 3 and 4 can be visualized as shown in Scheme 2.
In contrast, cyclization of 2 in ethanolic KOH yielded a product with molecular formula C 16 H 26 N 4 OS (MW = 322), which lacked in the IR spectrum the stretching absorption band for the nitrile group and retained carbonyl stretching band at 1725 cm -1 and weak absorption band for NH at 3165 cm -1 . This product was identified as the pyrazolo [2,3-a]1,3,5-triazine derivative 5 (Scheme 1).
The proclivity of 3 toward some electrophilic reagents such as aromatic aldehydes, heterocyclic aldehydes, heterocyclic ketone, phenyl isothiocyanate, and carbon disulfide was investigated. Refluxing compound 3 with salicylaldehyde in boiling ethanol in the presence of a catalytic amount of piperidine afforded the 2-iminocoumarin derivative 6 as orange crystals [18] (Scheme 3).
The imino coumarin derivative 6 was constructed on the basis of analytical and spectroscopic data. The IR spectrum of 6 displayed υ NH at 3220, 3216 cm -1 , υ C = O at 1698 cm -1 , υ C = N at 1669 cm -1 and showed the absence of a stretching absorption band for nitrile group. Furthermore, the mass spectrum of 6 showed the correct molecular ion peak characteristic for the molecular formula C 23 H 30 N 4 O 2 S at m/z = 426 (11.7%).
The structure of compound 7a was confirmed by the analytical and spectroscopic data. Thus, the IR spectrum of 7a revealed υ NH at 3144 cm -1 , υ C≡N at 2221 cm -1 , and υ C = O at 1697 cm -1 . The EI-MS spectrum of 7a showed the correct molecular ion peak at m/z = 552 (48.4%), which after lossing the acyl radical yielded the cation at m/z = 370 (93.5%).
The structure of 7b was deduced from the analytical and spectroscopic data. IR spectrum of compound 7b exhibited υ NH at 3244, 3202 cm -1 , υ C≡N at 2228 cm - Similarly, isatin easily condensed with the active methylene group in compound 3 upon refluxing with ethanol in the presence of piperidine to give 8 in good yield as red crystals (Scheme 3). The structure 8 was substantiated from the microanalytical and spectroscopic data.
When compound 3 was allowed to react with α-cyano-3,4-dimethoxy cinnamonitrile in refluxing ethanol with catalytic amount of piperidine, it afforded N-(5- The carbanion derived from 3 was added via Michael addition to the β-carbon of the arylidene malononitrile to give the Michael adduct, which eliminates malononitrile to give 9 via E1CB mechanism (Scheme 4).

Scheme 4.
A plausible mechanism for conversion of 3 to 9.
The IR spectrum of 10 displayed the coupling bands for NH 2 group at 3270, 3160 cm -1 , υ C = O at 1692 cm -1 , and υ C = N at 1622 cm -1 and lacked the stretching absorption band for the nitrile group. Moreover, 1 HNMR spectrum (DMSO-d 6 ) revealed the signals characterstic for deshielded one NH proton at δ 12.44 ppm, multiplet integrated for 3H at δ 7.67 ppm, doublet for 2H at δ 7.43-7.40 ppm corresponding to five aromatic protons, broad singlet for 2H representing the NH 2 group, and the signals upfield characteristic for the dodecanyl protons. Furthermore, the EI-MS of 10 detected the presence of a molecular ion peak at m/z = 489 (79%) together with the base peak at m/z = 307 (100%) characteristic for the radical cation [M-RCO . ]. The formation of 10 could be visualized as shown in Scheme 6. On the other hand, the reaction of 3 with phenyl isothiocyanate in ethanolic potassium hydroxide afforded after acidification the thiadiazole derivative 11 via the formation of intermediate B (Scheme 5). The structure 11 was confirmed by IR and mass spectra beside the correct elemental analysis. Thus, the IR spectrum displayed υ NH at 3203 cm -1 , υ C≡N at 2191 cm -1 , υ C = O at 1695 cm -1 and υ C = S at 1322 cm -1 . The EI-MS of 11 show the parent peak at m/z = 457 (37.3%).
Treatment of 3 with carbon disulfide and potassium hydroxide in dimethyl formamide (DMF) yielded the dipotassium salt C which in situ undergo alkylation with 1,2-dibromoethane to give the dithiolan derivative 12 (Scheme 5).
The structure 12 was confirmed from IR and MS spectra. Thus, the IR spectrum of compound 12 revealed υ NH (br) at 3153 cm -1 , υ C≡N at 2201 cm -1 , and υ C = O at 1696 cm -1 . The mass spectrum of 12 displayed the correct molecular ion at m/z = 424 (14.6%) and the radical cation of m/z = 242 (68.3%) obtained upon loss of R-C . =O radical followed by H-abstraction.
Compound 13 showed the disappearance of the stretching absorption band for the nitrile group and displayed a new carbonyl band at 1730 cm -1 for thiazolidinone beside the carbonyl group for dodecanoyl group at 1690 cm -1 . Furthermore, the mass spectrum of 13 showed the correct molecular ion peak at m/z = 396 (23.4%) together with the base peak at m/z = 214 (100%) characteristic for the radical cation [M + -R-CO].

CONCLUSION
Novel 2,5-disubstituted 1,3,4-thiadiazoles were prepared via cyclization of the corresponding thiosemicarbazide followed by the reaction with some electrophilic reagents. The synthesized compounds were obtained in good yields.

EXPERIMENTAL
All reagents were obtained from commercial sources and used without further purification. Melting-points are uncorrected and were measured by an electric melting-point apparatus (G-K). The IR spectra were recorded on a Pye-Unicam SP1200 spectrophotometer using the KBr Wafer technique. The 1 HNMR spectra were determined on a Varian Gemini 300-MHz NMR spectrophotometer using CDCl 3 or dinethylsulfoxide (DMSO-d 6 ) as solvent with tetramethylsilane (TMS) as an internal standard. All chemical shifts are in parts per million (ppm) downfield from TMS. The elemental analyses were carried out in Faculty of Science, Ain Shams University. Mass spectra (MS) were recorded on a Shimadzu GC-MS QP1000EX instrument in the Microanalytical Laboratory, Cairo University. Monitoring of the progress of all reactions was carried out by thin-layer chromatography (TLC).

Synthesis of 1-(2-Cyanoacetyl)-4-dodecanoylthiosemicarbazide 2
Cyanoacetohydrazide (0.99 g, 0.01 mol) in boiling dioxane was added to a mixture of lauroyl chloride (2.3 mL, 0.01 mol) and ammonium thiocyanate (0.76 g, 0.01 mol) in dioxane (20 mL) and then the whole mixture was refluxed for 30 min. The colorless solid deposited while hot was collected by filtration and then recrystallized from toluene to give 2 as colorless crystals;

SUPPORTING INFORMATION
Full experimental details and spectroscopic data for compounds 3-13 can be found via the Supplementary Content section of this article's Web page.