Synthesis of [1,3,2]dithiazolo[4,5-b ][1,2,5]oxadiazolo[3,4-e ]pyrazines

The reaction temperature has a strong impact on the results of chlorination of 5,6-bis( tert - butylthio)[1,2,5]oxadiazolo[3,4-b ]pyrazine that is readily prepared from 5,6-dichloro[1,2,5]oxadiazolo[3,4-b ]pyrazine and sodium tert -butylsulfide. Mono-and bis(sulfenylchlorides) were selectively obtained in high yield and their structure was confirmed by the reaction with morpholine. Treatment of [1,2,5]oxadiazolo[3,4-b ]pyrazine-5,6-disulfenyl dichloride with primary aliphatic amines and benzylamine afforded N -substituted [1,3,2]dithiazolo[4,5-b ][1,2,5]oxadiazolo[3,4-e ]pyrazines in moderate yields. Novel pentacyclic [1,2,5]oxadiazolo[3'',4'':5',6']pyrazino[2',3':5,6][1,2,4]thiadiazino[3,4-b ][1,3]benzothiazole, whose structure was confirmed by X-ray diffraction, was obtained by the reaction of this disulfenyl dichloride with 2-aminobenzothiazole.

The preparation of dithiol 6a was described before, but neither detailed procedure, nor its spectral evidence were reported. 15We have studied the reaction between dichlorooxadiazolopiperazine 7 and sodium sulfide.Unfortunately under all the tested conditions (treatment these reagents in ethanol, water, or their mixtures) only unidentified products were isolated.IR spectra of the products revealed bands of amido groups (about 1560 cm -1 ) which signify the hydrolysis (at least partly) of chloro substituent to pyrazinone.We attempted to prepare dithiol 6a by the following route: nucleophilic substitution of the reactive chlorine atoms in 6a by thiourea obtaining the 2,3-diisothiuronium salt 8 with its subsequent hydrolysis by sodium hydroxide according to the method recently proposed for 2,3-dichloropyrazine 16 and 2,3dichloroquinoxaline. 17 However, treatment of 5,6-dichloro [1,2,5]oxadiazolo [3,4-b]pyrazine 7 with thiourea in ethanol led to formation of a product which decomposed due to alkali conditions.
Another methodology for the synthesis of disulfenyl dichlorides proposed by Rawson 18 includes reaction of ortho-dichloroderivatives with "Less' reagent" (Bu t SNa) resulting in the formation of stable dithiolate derivatives, such as 6c.Large size of the tert-butyl group allows the thiolate to be readily deprotected by chlorination with chlorine at 0 °C to generate the desired disulfenyl dichlorides in high yields.Treatment of a substituted dichlorooxadiazolopiperazine 7 with two equivalents of Bu t SNa in THF at -10 °C yielded the corresponding bis(tert-butylthio) derivative 6c in 87% yield (Scheme 2).Scheme 2. Synthesis of 5,6-bis(tert-butylthio) [1,2,5]oxadiazolo [3,4-b]pyrazine 6c.
Dithiolate 6c was found inert towards sulfuryl chloride, starting material was isolated from the reaction mixture in practically quantitative yield.Chlorination of dithiolate 6c with chlorine in dichloromethane led to mixtures of sulfenylchlorides 9-11.Our attempts to isolate pure sulfenylchlorides from these mixtures were unsuccessful which was not surprising bearing in mind that normally aromatic and heteroaromatic disulfenyl dichlorides are unstable, and used in further reactions in situ (see [2] and references therein.In order to investigate this reaction in more detail, we treated the chlorinated mixtures with morpholine to get more stable Smorpholino derivatives, which were isolated by chromatography.Three S-morpholino derivatives 12-14 which derived from monochlorinated product 9, disulfenyl dichloride 10 and mono-sulfenylchloride 11, respectively, were obtained and their structures have been confirmed by elemental analysis, 1 H and 13 C NMR, IR spectroscopy and mass spectrometry.Our standard procedure was to pass a continuous chlorine stream through a solution of dithiolate 6c (0.5 mmol) in dichloromethane (10 ml) at the temperature listed in Table 1 followed by evaporation of the reaction mixture at 0 °C and quenching of the residue solution in dichloromethane (10 ml) with morpholine (1 mmol) at 0 °C.The product yields were strongly dependent on the temperature and duration of chlorination of dithiolate 6c.The reaction conditions and yields of morpholine derivatives 12-14 and the starting material 6c are given in Table 1.No chlorination occurs at 0-2 °C, and the starting 6c was isolated from the reaction mixture virtually unchanged (entry 1).The reaction started at 5 °C, chlorination at 5-10 °C gave exclusively mono-chlorinated product 9 (entries 2 and 3), increasing the temperature to 12-15 °C led to reaction of the second S-Bu t group, albeit slowly.For the formation of disulfenyl dichloride 10 chlorination at 15-17 °C is optimal: the yield of di(S-morpholino) adduct 13 is nearly quantitative (entry 6).Chlorination at higher temperatures (up to 20-25 °C) resulted in the substitution of one sulfenylchloride group by chlorine atom (entries 7 and 8; compound 11).This reaction is not described in the literature, and it might be envisaged that chlorine attacks the carbon atom of the pyrazine ring with displacement of sulfur dichloride (SCl2).The structure of sulfenylchlorides 9-11 was also confirmed by 1 H and 13 C NMR spectroscopy and mass spectrometry.Treatment of disulfenyl dichloride 10 with 1 equivalent of trimethylsilylazide in chloroform or in acetonitrile at room temperature gave a mixture of unidentified compounds.The desired 1,3,2-dithiazolium salt 15 did not form in any of these reactions.In order to obtain substituted [1,3,2] [3,4-e]pyrazines 1 a systematic study of the reactions between disulfenyl dichloride 10 with primary amines has been undertaken.Primary aromatic amines with electron withdrawing chloro or nitrogroups did not react with disulfenyl dichloride 10 in dichloromethane; starting amines were isolated from the reaction mixtures unchanged.Reaction with more basic aniline or 1-naphthylamine in dichloromethane even at low temperature (-10 °C) resulted in the decomposition of disulfenyl dichloride 10.
Reaction of disulfenyl dichloride 10 with benzylamine in dichloromethane in the presence of 2 equivalents of triethylamine afforded a novel compound, as a yellow solid which according to the mass spectra, elemental analysis and 1 H and 13 C NMR data is 1,3,2-dithiazole 1a.Disulfenyl dichloride 10 reacted with other primary aliphatic amines in a similar manner giving the corresponding 1,3,2-dithiazoles 1 in moderate yields (Scheme 5).

Scheme 5. Synthesis of substituted
Treatment of disulfenyl dichloride 10 with heterocyclic 2-aminobenzothiazole in presence of triethylamine unexpectedly gave an orange solid in a low yield, to which structure 16 (C11H4N6OS2) was assigned (Scheme 6).According to the mass spectrometry, 13 C and 1 H NMR data, and elemental analysis it is formally a product of amine addition with elimination of sulfur and two HCl molecules.Finally its structure was confirmed by X-ray diffraction analysis (Figure 2).The formation of the previously unknown pentacyclic system 16 can be explained by addition of 2-aminobenzothiazole in its imino-form to disulfenyl dilchloride 10 with subsequent elimination of sulfur atom resulting in virtually planar and stable heterocyclic compound.
The pentacyclic structure 16 was confirmed by X-ray diffraction analysis.According to the XRD data, the molecule of 16 is almost flat with the mean deviation of the atoms from its plane not exceeding 0.025Å.The bond length distribution for each of the heterocycles is in the range of the expected values (Figure 2).The flat conformation of the whole molecule can be stabilized by either intra-or intermolecular interactions.Indeed, flattering of the pentacyclic compound is accompanied by the shortening of the C(17)-H(17)….N(6) contact (C…N 2.799(4), H…N 2.22 Å, CHN 111 o ).On the other hand, the molecules in the crystal of 16 are arranged in columns in the "head to tail" manner; the formation of the shortened C…C contacts (C( 7)…C (20), C( 16)…C( 16), C(11)…C( 18)) with the interatomic distances varying in the range of 3.28-3.34Åunambiguously indicate the presence of a significant overlap of the corresponding heterocyclic moieties.To estimate the role of the above inter-and intramolecular interactions in the stabilization of the planar conformation of 16, we have performed the DFT calculation (M06-2X/6-311G**) of an isolated molecule.The optimized geometry was nearly the same as that in the solid state (see SI) .After the geometry optimization, the molecule 16 was found to be slightly non-planar and bent along the N(10)-C (11) bondthe dihedral angle between the two corresponding heterocyclic moieties is equal to 5.5 o .Despite this bending, the intramolecular contact is characterized by almost the same geometric parameters as those in a crystal (C…N 2.813, H…N 2.19 Å, CHN 114 o ).Thus, the main contribution to the pentacycle flattering is the stacking interaction that is characterized by the maximum overlap between the fragments that are linked by the N(10)-C(11) bond.
In order to prepare S-oxides of 1,3,2-dithiazoles compounds 1 were treated with mchloroperoxybenzoic acid in chloroform.No reaction occurred at room temperature but reflux of dithiazoles 1 in chloroform resulted in their slow decomposition and no S-oxides were detected in the reaction mixture.

Conclusions
Heterocyclic fused 1,3,2-dithiazoles were prepared from the reaction of [1,2,5]oxadiazolo [3,4b]pyrazine-5,6-disulfenyl dichloride and primary aliphatic amines and benzylamine.Under the same conditions reaction with 2-aminobenzothiazole unexpectedly afforded a new pentacyclic oxadiazolopyrazinothiadiazinobenzothiazole.For the selective synthesis of this disulfenyl dichloride from the corresponding bis(tert-butylthio) derivative a careful control of the reaction temperature is required; reaction at lower temperatures led to mono-sulfenyl chloride, while at higher temperatures sulfenyl chloride group is substituted by a chlorine atom.

General procedure for reaction of disulfenyl dichloride (10) with primary amines
A solution of triethylamine (0.10 g, 1 mmol) in dichloromethane (2 mL) and primary amine (0.5 mmol) in dichloromethane (2 mL) were added successively at -40 ÷ -35 °C to a solution of disulfenyl dichloride 10 obtained from dithiolate 6c (149 mg, 0.5 mmol) in dichloromethane (10 mL).The reaction mixture was stirred for 1 h at this temperature and 1 h at room temperature.Solvents were evaporated under reduced pressure and the residue was separated by column chromatography (Silica gel Merck 60, light petroleum, and then light petroleum-CH2Cl2 mixtures).were measured with a Bruker SMART APEX2 CCD diffractometer [(Mo K) = 0.71072 Å, scans, 2 < 58], and 2945 independent reflections [Rint = 0.0364] were used in further refinement.The structure was solved by a direct method and refined by the full-matrix leastsquares technique against F 2 in the anisotropic-isotropic approximation.The hydrogen atoms were located from the Fourier synthesis of electron density and refined in the isotropic approximation.For 16, the refinement converged to wR2 = 0.0955 and GOF = 1.033 for all independent reflections (R1 = 0.0399 was calculated against F for 2357 observed reflections with I > 2(I)).All calculations were performed with the SHELXTL software package. 19CCDC 829170 contains the supplementary crystallographic data for 16.These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge, CB21EZ, UK; fax: (+44) 1223-336033; or deposit@ccdc.cam.ac.uk).The DFT calculations of the isolated molecule of 16 was performed with the Gaussian09 program package 20 using the M06-2X functional.Full optimization of the geometry was carried starting from the X-ray structural data with the 6-311G** basis set for all atoms.The extremely tight threshold limits of 2•10 -6 and 6•10 -6 a.u.were applied for the maximum force and displacement, respectively.