New chemistry of bis[1,2]dithiolo[1,4]thiazines and bis[1,2]dithiolopyrroles

The new long-chain or branched-chain N -alkyl bisdithiolothiazines 2a , b , 3a , c , and 4a , c have been prepared by the appropriate one-pot reaction of the corresponding N - alkyldiisopropylamines and disulfur dichloride. The bisdithiolopyrroles 5a-f were obtained by thermal sulfur extrusion from their corresponding bisdithiolothiazines or by an alternative and faster method consisting of S -oxidation by dimethyldioxyrane and SO extrusion. The cycloadditions of a bisdithiolothiazine ketothione and benzyne or p -tolylsulfonylacetylene were studied and the new cycloadducts 7 and 9 ( Z + E ) were characterized.


Introduction
Although many sulfur-containing heterocycles have been known from the early times of organic ohemistry, it has not been until recently that some of these compounds have found their most important applications.The discovery of superconducting tetrathiafulvalene charge-transfer complexes 1 and molecular switches, 2 thiazole and thiadiazole liquid crystals 3 and thiophene nonlinear optical materials 4 has stimulated the search for new materials based on sulfur heterocycles.On the other hand, the study of many bioactive compounds, as for example Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], 5 and other natural and synthetic 1,2dithiolethiones, 6 has drawn attention to the role of polysulfur heterocycles in the field of pharmaceutical chemistry.The development of new general methods for the synthesis of sulfur heterocycles has thus become an issue of intense research.In this context we have discovered that N-ethyldiisopropylamine (Hünig′s base), and other tertiary amines containing isopropyl groups, react under mild conditions with disulfur dichloride to give bis [1,2]dithiolo [1,4]thiazines 7 and bis [1,2]dithiolopyrroles. 8y means of this new reaction we have prepared some examples of these heterocyclic systems (Scheme 1), constituting a very short and convenient preparative method in some instances starting from all commercial reagents.These heterocycles, containing the 1,2-dithiole-3-thione moiety could be further functionalized by its cycloaddition with different dienophiles and 1,3dipolar reagents.In order to assess the generality of the reaction, we now report some new aspects of the chemistry of these novel heterocycles.

Scheme 3
We have previously shown that bisdithiolothiazines readily extrude sulfur, to give fused bisdithiolopyrroles. 8,10 This reaction usually proceeds by simply refluxing a solution of the substrate in a high boiling point solvent, such as chlorobenzene, for a period ranging from several minutes to a few hours.Nevertheless, some particular cases, for different reasons, are reluctant to extrude sulfur.For example, the transformation of N-(2-chloroethyl)-substituted bisdithiolothiazine 3e into the corresponding pyrrole was complete only after 7 days of refluxing a chlorobenzene solution of the starting material.This is probably due to an attractive interaction between the chlorine and the thiazine sulfur atoms that contributes to stabilize the structure conformation, as deduced from calculations using ab initio density functional theory methods 11 and the measured X-ray crystal diffraction Cl•••S distance of 3.85 Å. 12 On the other hand, the N-unsubstituted parent bisdithiolothiazine 3g did not extrude sulfur at all, even after long periods of heating in refluxing chlorobenzene. 13We then envisaged a new method for sulfur extrusion that could work with the more reluctant cases.Thiazines have been reported to react with mild oxidizing reagents to give the corresponding thiazine oxides and dioxides. 14The electron-withdrawing effect of oxygen atoms on sulfur makes SO and SO 2 much better leaving groups than S, making sulfur extrusion a much easier process.Hence, we treated N-laurylbisdithiolothiazine 3a with 1 equivalent of dimethyldioxirane in benzene, followed by reflux until all the starting material had disappeared, as monitored by tlc.After the work-up, the only isolable product was the bisdithiolopyrrole 5a.We tried different amounts of the oxidizing reagent and reaction times, and the best results were obtained with 1.4 equivalents of DMD and refluxing the reaction mixture for 25 minutes.In these conditions, the pyrrole 5a was obtained, after chromatography, in moderate yield (38%).This relatively low yield is probably due to some oxidation of the sulfur atoms on the dithiole ring, followed by decomposition.Though, if a smaller amount of DMD is used, some starting material remains unreacted and the yield decreases; on the other hand, if the amount of DMD is increased, the yield also drops, due to over-oxidation.We applied this reaction to 3c as well as to other substrates.The best results are summarized in Table 1, along with the experimental or bibliographic results from thermal sulfur extrusion.Remarkably, the reaction of N-(2-chloroethyl)-substituted dithiolothiazine 3e (entry 4) was performed in only 1 h, in contrast with the 7 days reaction time in thermal conditions, though some starting material was recovered along with the desulfuration product.We have shown that bisdithiolopyrroles that contain one or two exocyclic sulfur atoms are able to undergo 1,3-dipolar cycloadditions with dimethyl acetylenedicarboxylate, yielding complex polycyclic 1,3-dithioles. 8Bisdithiolothiazine ketothiones should also react with activated triple bonds to give new polycyclic systems.With this in mind, we essayed the reaction of dithiolothiazine ketothione 4h with benzyne.In the first experiment, we used the classic conditions to generate benzyne from anthranilic acid 16 in the presence of dithiolothiazine 4f.
Unfortunately, this produced the total decomposition of 4f.Other methods for the in situ synthesis of benzyne, such as oxidation of 1-aminobenzotriazol with different oxidizing agents: lead tetraacetate, 17 N-iodosuccinimide 18 or BAIB, or the treatment of o-trimethylsilylphenyl triflate with cesium fluoride and catalytic paladium tetrakis(triphenyl)phosphine, led to the decomposition of 4f.Nevertheless, the Kitamura′s method, 19 starting from the orthohydroxydimethylsilyl-substituted hypervalent iodine salt 6, provided a very mild and convenient method to generate benzyne in the presence of 4f, from which the immediate formation of a cycloaddition product was observed by tlc.Work up and purification by column chromatography provided the benzodithiolane derivative 7 as a red solid (71%) characterized by spectroscopy.(Scheme 5).The acetylene group behaves as a good dipolarophile when it is activated by a sulfone group.Therefore we submitted dithiolothiazine 4f to reaction with excess of ethynyl p-tolyl sulfone 8 in dichloromethane, in the presence of scandium triflate [Sc(OTf) 3 ], which is a good catalyst for cycloadditions.After work-up and column chromatography of reaction residue we separated the new dithiolane derivative 9 as a red solid, mixture of geometric isomers (56%), which was characterized by spectroscopy (Scheme 6).The 1 H-NMR spectrum of 9 showed two distinct signals corresponding to the 1,3-dithiole proton (δ 7.9 and 7.7) and two groups of two double quartets partially superimposed at δ 3.5 and 3.2, corresponding to the diastereotopic methylene group placed on the nitrogen which is part of the asymmetric folded thiazine ring, that undergoes restricted inversion at room temperature.

Conclusions
We have extended the previous methodology in the direct conversion of Nalkyldiisopropylamines into N-alkylbisdithiolothiazines in one pot to the synthesis of the long chain or branched alkyl derivatives, which were hitherto unknown, and developed an alternative way to the preparation of N-alkylbisdithiolopyrroles by selective S-oxidation of the thiazine sulfur with dimethyldioxyrane and thermal extrusion of SO from the sulfoxide.In addition, we have studied the cycloaddition of a bisdithiolothiazine ketothione with benzyne and discovered that only the benzyne prepared by the mildest Kitamura′s method was suitable for the cycloaddition on our substrate.We have also studied the catalyzed cycloaddition of acetylene activated by a sulfone group on the same substrate and obtained a new dithiolane derivative as the Z + E mixture of isomers.This, and the benzodithiolane obtained in the latter cycloaddition, are compounds that combine electron acceptors and donor in the same molecule, and can be useful as organic materials.

Scheme 4 Table 1 .
Sulfur extrusion of thiazines 3a-g a A 32% of starting material 3e was also recovered.Issue in Honor