Synthesis of 1,3,4-Thiadiazole, 1,3,4-Thiadiazine, 1,3,6-Thia-diazepane and Quinoxaline Derivatives from Symmetrical Dithiobiureas and Thioureidoethylthiourea Derivatives

Reactions of N,N′-disubstituted hydrazinecarbothioamides 8a-c and substituted thioureidoethylthioureas 9a-c with 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil, 10a) and 2,3,5,6-tetrabromo-1,4-benzoquinone (bromanil, 10b) to form N,N′-disubstituted [1,3,4]thiadiazole-2,5-diamines 11a-c, 6,7-dichloro-3-substituted amino-1H-benzo[1,3,4]-thiadiazine-5,8-diones 12a-c, 2,3,7,8-tetrahalothianthrene-1,4,6,9-tetraones 13a,b, 5,6,8-trihalo-7-oxo-3,7-dihydro-2H-quinoxaline-1-carbothioic acid substituted amides 14a-c, 15a-c and 7-substituted imino-[1,3,6]thiadiazepane-3-thiones 16a-c are reported. Rationales for the observed conversions are presented.


Scheme 1
In view of these discrepancies, Katritzky and co-workers subsequently reexamined some of those reactions [20]. Although the product reported to have been isolated by Matsuoka et al. was indeed formed, in all cases the 1,4-dithiine was accompanied by the corresponding 1,3-thiazole, although in some cases product separation was difficult.
14: X = Cl 15: X = Br As an example, the structural assignment of 12a was supported by the following spectral data: in its 13 C-NMR spectrum, the characteristic absorption signal of the carbonyl carbon atoms of chloranil (10a) appeared at δ = 170.20, 171.36 ppm [29]. The 1 H-NMR spectrum of 12a showed two broad signals at 7.68 and 8.80 ppm, due to the NH attached to the phenyl ring and the thiadiazine-NH, respectively, in addition to the phenyl protons. The IR spectrum of 12a (KBr disk) showed sharp bands at 3330, 3270 and 1680 cm -1 for the secondary amino and carbonyl groups respectively. The thianthrenetetraones 13a,b exhibited absorptions at 1700-1695 cm -1 for the quinine carbonyl groups. The 13 C-NMR spectra of 13a,b showed absorption signals around 171.36 -170.86 ppm for the chloranil or bromanil carbonyl carbon atoms. The formation of 13a,b was further confirmed by mass spectrometry. Besides the molecular ions at 416/412 or 594/590, the characteristic fragment ion patterns of the substituted tetrahalo compounds were observed [30].
Formation of these products may be rationalized by the mechanism shown in Scheme 2: an unstable CTC is formed followed by the formation of radicals 8 . and 10-H . . Two routes could be suggested for the formation of compounds 11-13 after the recombination of the two radicals 8 . and 10- It has been reported that ethylenediamine upon reaction with allylisothiocyanate furnishes a linear thiourea, which in turn is cyclized to a bisthiazoline [31]. The present work was also undertaken to examine the reactions of 9a-c with 10a,b. Thus, two equivalents of thioureidoethylthiourea derivatives 9a-c reacted with 10a,b in THF at room temperature to afford substituted imino-[1,3,6]-thiadiazepane-2-thiones 16a-c as minor (14-19%) and trihalo-7-oxo-quinoxaline-1-carbothioic acid substituted amides 14a-c/15a-c as major products (41-49%), in addition to the corresponding dihydrobenzoquinone derivatives. The structures of 14a-c and 15a-c were confirmed on the basis of elemental analyses, mass spectra, 1 H-and 13 C-NMR data. The IR spectra of 14a-c/15a-c showed characteristic absorption bands for the secondary-NH between 3330 and 3310 cm -1 and between 1690-1680 cm -1 for the C=O groups. The 1 H-NMR spectrum of 14a shows the resonances of the methylene protons at C3 and C2 in the δ = 3.46 -3.60 and 3.64 -3.87 ppm range, respectively. The presence of methylene groups is also evident from the 13 C-DEPT-NMR spectrum, which exhibits negative signals at δ = 48.77 and 55.33 ppm. In addition, the 1 H-NMR spectrum exhibited a broad singlet centered at 9.69 ppm due to the NH-attached to phenyl and C=S groups. The decoupled carbon spectrum of 14a showed signals at δ = 170.17 and 180.34 ppm, assigned to C=O and C=S, respectively [30,32].
The formation of quinoxaline products 14 and 15 may be rationalized through the successive substitution of one chlorine atom and elimination of a molecule of substituted isothiocyanate followed by cyclization via a condensation reaction (Scheme 2).

General
All the melting points were determined in open glass capillaries on a Gallenkamp melting point apparatus and are uncorrected. The IR spectra were recorded with a Shimadzu 408 or Bruker Vector 22 FT-IR spectrophotometers using potassium bromide pellets. A Bruker WM 300 spectrometer was used to determine 1 H-(300.13 MHz) and 13 C-(75.47 MHz) NMR spectra. Assignment of carbon resonances have been supported by DEPT experiments. Mass spectra were obtained with a Varian MAT 311 doubly focusing instrument using electron impact ionization (70 eV). Elemental analyses were determined at the Microanalytical Center, Cairo University, Egypt. UV/Vis spectra were recorded on a Perkin-Elmer Lambda 2-spectrophotometer equipped with a thermostated cell. Preparative thin layer chromatography (plc) was carried out on 1 mm thick layers of silica gel slurry (Merck Pf 254 ) applied on 48 cm wide x 20 cm high glass plates using the solvents mentioned below. Zones were detected by quenching of fluorescence upon exposure to 254 nm light and the compounds were extracted from the plates with acetone.
A solution of 8a-c (2.0 mmol) in anhydrous THF (20 mL) was added dropwise with stirring to a solution of chloranil (10a) or bromanil (10b) (1.0 mmol) in the same solvent (20 mL). The colour of the reaction changed gradually from deep green to a blue colour. Stirring was continued for 48 hours with admission of air to complete the reaction. The reaction mixture was filtered and the blue precipitate was washed several times with cold THF and identified as the tetrahalothianthrenetetraones 13a,b. The filtrate was concentrated in vacuum and the residue separated by plc using cyclohexane/ethyl acetate (2:1) mixture into three zones. The fastest moving zone contained the thiadiazoles 11a-c, the second zone, compounds 12a-c and the slowest migrating zone contained the dihdrobenzoquinones 14-H 2 or 15-H 2 . The zones were extracted with acetone.   [1,3,4] Reactions of 9a-c with chloranil (10a) and bromanil (10b).

3-Allylamino-6,7-dichloro-1H-benzo
A solution of 9a-c (1.0 mmol) in anhydrous THF (15 mL) was added dropwise with stirring to a solution of 10a,b (1.0 mmol) in anhydrous THF (20 mL). The mixture was heated under reflux for 5 hours, during which it turned from yellow into reddish orange. The mixture was concentrated under vacuum and the residue separated by plc using cyclohexane/ethyl acetate (3:1) as developing solvent to give numerous coloured zones, three of which (with the highest intensity) were extracted and removed. The fastest migrating one, which quenched all indicator fluorescence upon exposure to 254 nm UVlight, contained the thiadiazepanes 16a-c, the second zone (which was always characterized by an orange colour) contained the quinoxalines 14a-c and 15a-c, while the third zone contained the dihydrobenzoquinones 14-H 2 and 15-H 2 .