Synthesis and Reactivity of 3H-1,2-dithiole-3-thiones

3H-1,2-Dithiole-3-thiones are among the best studied classes of polysulfur-containing heterocycles due to the almost explosive recent interest in these compounds as sources of hydrogen sulfide as an endogenously produced gaseous signaling molecule. This review covers the recent developments in the synthesis of these heterocycles, including both well-known procedures and important novel transformations for building the 1,2-dithiole-3-thione ring. Diverse ring transformations of 3H-1,2-dithiole-3-thiones into various heterocyclic systems through 1,3-dipolar cycloaddition, replacement of one or two sulfur atoms to form carbon- and carbon-nitrogen containing moieties, and other unexpected reactions are considered.

Hydrogen sulfide (H 2 S) is considered to be the third endogenously produced gaseous signaling molecule, or gasotransmitter, along with carbon monoxide (CO) and nitrogen monoxide (NO) [16]. Cellular H 2 S biosynthesized by enzymatic and non-enzymatic pathways regulates important functions of the cardiovascular, immune, nervous, respiratory and gastrointestinal systems and is involved in a number of diseases, including Down syndrome, Alzheimer's, and Parkinson's diseases [17]. Although there are a great variety of H 2 S donors, one of the most extensively studied H 2 S donors are 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH, 6) and its derivatives that contain the H 2 S-releasing dithiolethione moiety.
The second reason for the interest in 1,2-dithioles is the rich chemistry of these compounds which until recently was associated mainly with 1,2-dithiole-3-thiones. For example, many 1,2-dithiole-3-thiones have been employed as precursors for the synthesis of tetrathiafulvalene vinylogues that enhance the nonlinear optical properties for the creation of organic electronic conductors [18], photoconductive materials [19,20], or semiconducting polymers [21].
Therefore, special attention was paid to the development of efficient and reliable methods for the synthesis of 3H-1,2-dithiole-3-thiones and to their reactivity. A number of reviews deal with the general aspects of the chemistry of 1,2-dithioles, such as the corresponding chapters in Comprehensive Heterocyclic Chemistry II and III [22,23] and other
More recently it was shown that in some cases, for example, for 3-oxoesters containing a pyrazinyl group at C-3, this procedure can result in lower yields of 3H-1,2-dithiole-3thiones, up to 39% [28]. Therefore, a number of attempts were made to modify this method, i.e., to replace Lawesson's reagent with cheaper P 4 S 10 and to avoid the use of elemental sulfur that complicated the purification of the final heterocycles. It was found that 2-(aryl)-3-oxo-3-(aryl)propanoates reacted with P 4 S 10 in toluene under reflux conditions to give the corresponding 3H-1,2-dithiole-3-thiones in acceptable yields ( Figure 2) [29]. Unfortunately, the use of this protocol for 3-oxo-3-(pyrazin-2-yl)propanoates still gave pyrazinyldithiole-3-thiones in low yields (5-16%) [30].  The most efficient procedure was developed by Curphey [31]. A combination of P 4 S 10 and sulfur in the presence of hexamethyldisiloxane (HMDO) efficiently converted 3-oxoesters to dithiolethiones. In general, the yields of dithiolethiones obtained with P 4 S 10 /S 8 /HMDO mixtures were higher than those obtained with Lawesson's reagent (Scheme 2). Addition of hexamethyldisiloxane (HMDO) to a P 4 S 10 -sulfur mixture both significantly increased the yield of dithiolethione 1 and greatly simplified the workup of the reaction mixture. Determination of the amount of HMDO remaining by the end of the reaction showed that about four equivalents of the disiloxane were consumed per one equivalent of P 4 S 10 . The role of HMDO can be explained as follows: in the presence of HMDO, highly electrophilic phosphorus species were converted to harmless silylated phosphates, thereby increasing the yield of the thionation product. On the other hand, removal of elemental sulfur from the reaction mixture reduced the yield of dithiolethiones, in agreement with the beneficial effects of sulfur observed in the conversion of 3-oxoesters to dithiolethiones by Lawesson's reagent. The details of how sulfur acts to increase the yields of these dithiolethiones are not clear. Many other 3H-1,2-dithiole-3-thiones have been successfully prepared using this protocol [32]. Scheme 2. Synthesis of 3H-1,2-dithiole-3-thiones by the reaction of 3-oxoesters with sulfur, P 4 S 10 and HMDO.

Synthesis of 3H-1,2-dithiole-3-thiones from α-Enolic Dithioesters and Related Compounds
Dialkyl malonates, α-enolic dithioesters or α-enolic dithioic acids can be successfully employed for the synthesis of various 3H-1,2-dithiole-3-thiones. Treatment of dialkyl malonates with a mixture of elemental sulfur and P 2 S 5 in refluxing xylene resulted in 4-substituted 5-alkylthio-3H-1,2-dithiole-3-thiones as the major products [33,34]. The presence of a 2-mercaptobenzothiazole/ZnO mixture as the catalyst is essential for the reaction to occur successfully (Scheme 3). The result strongly depended on the structure of malonate esters. Malonate esters of primary alcohols gave moderate yields of dithiolethiones, while malonate esters of secondary alcohols did not. While dialkyl malonates containing Me, Ph, Bn, OMe and Cl substituents at position 2 successfully withstood the reaction conditions, 2-bromo-and 2-nitro-derivatives did not give the desired products. If dithiolmalonic esters obtained from malonyl dichloride and the corresponding thiols were involved in the reaction with P 4 S 10 , 5-alkylthio-3H-1,2-dithiole-3-thiones were isolated from the reaction mixtures [35]. It was found that the use of Lawesson's reagent as the sulfurating agent resulted in better yields of dithiolethiones (Scheme 4). A 2-mercaptobenzothiazole/ZnO mixture was successfully employed as the catalyst in these reactions. Yet another attractive approach to 1,2-dithiole-3-thiones based on various ketones via dianions of 3-oxodithioic acids was suggested by Curpey [36]. It was shown that the reaction of ketones with CS 2 and two equivalents of KH in THF-N,N'-dimethylpropyleneurea (DMPU) solutions resulted in dianions of 3-oxodithioic acids. Sequential treatment of these dianions with hexamethyldisilathiane and hexachloroethane as the oxidizing agent gave 4,5-disubstituted 1,2-dithiole-3-thiones in good to excellent yields (Scheme 5). The use of a strong base such as KH and a dipolar aprotic cosolvent, either HMPA or DMPU, is necessary to convert the monoanion formed initially into a dianion. Other oxidizing agents such as bromine or iodine gave similar or slightly lower yields of 1,2-dithiole-3-thiones.

Synthesis of 3H-1,2-dithiole-3-thiones from Iso-Propenyl Derivatives
Dehydrogenation and sulfuration of an iso-propenyl or iso-propyl group with phosphorus pentasulfide or elemental sulfur is the most awaited method that has been used for a long time [41]. However, it has the disadvantage of drastic reaction conditions (heating up to 200 • C) and has been rarely used lately.

Synthesis of 3H-1,2-dithiole-3-thiones from Alkynes
4-Mercapto-5-substituted 3H-1,2-dithiole-3-thiones can be easily prepared by a onepot procedure from terminal alkynes [45]. Deprotonation of terminal alkynes with BuLi followed by treatment with carbon disulfide resulted in alkynyldithiocarboxylates, which were then treated with elemental sulfur to give 4-mercapto derivatives after acidic workup (Scheme 12). If the reaction mixtures were quenched with methyl iodide rather than HCl, stable 4-methylthio derivatives were isolated in similar yields. Surprisingly, if isopropylamine is added to the reaction mixture instead of HCl, the reaction can be stopped with the formation of 5-substituted 1,2-dithiole-3-thiones [46]. The method is very convenient and a number of 5-substituted 1,2-dithiole-3-thiones were successfully synthesized (Scheme 13). Along with the formation of a heterocyclic ring, trimethylsilylacetylene underwent desilylation in the reaction to give the parent heterocycle in a moderate yield. Scheme 13. Synthesis of 5-substituted 3H-1,2-dithiole-3-thiones from alkynes. 5-Phenyl-3H-1,2-dithiole-3-thione was prepared from molybdenum dithiopropiolato complexes 7 [47]. Treatment of these complexes with trimethylamine-N-oxide in MeCN resulted in 1,2-dithiole-3-thione (Scheme 14). The authors assumed the formation of intermediate molybdenum oxo-complexes, which were isolated after the first stage and then subjected to hydration with water from Me 3 NO·H 2 O (the use of anhydrous TMNO did not give dithiolethione). The authors did not explain where the third sulfur atom of dithiolethione comes from, and even more surprisingly, addition of elemental sulfur did not improve the yields of 5-phenyl-3H-1,2-dithiole-3-thione. Zhang's team recently published two efficient syntheses of monosubstituted 1,2dithiole-3-thiones from internal alkynes. Copper catalyzed defluorinating thioannulation of aryl trifluoropropynes using elemental sulfur as the only sulfur source proved to be a simple and practical strategy for the preparation of 5-aryl-3H-1,2-dithiole-3-thiones (Scheme 15) [48]. Specific features of this reaction include the efficient formation of multiple C-S bonds due to cleavage of C-F bonds in the CF 3 group, a wide scope of substrates, and a high tolerance to functional groups; 1,2-dithiole-3-thiones are formed in moderate to high yields on treatment of trifluoropropynes with S 8 and Cs 2 CO 3 in the presence of CuBr and TMEDA in DMF at 120 • C. Yet another approach involves the copper-catalyzed aerobic oxidative sulfuration and annulation of propargylamines with elemental sulfur in diethylformamide (DEF) [49]. The tandem reaction includes the cleavage of the C−N bond and formation of multiple C−S bonds to give 5-aryl-3H-1,2-dithiole-3-thiones in good to excellent yields with perfect electron-rich and electron-poor aryl (hetaryl) group tolerance (Scheme 16). Various secondary and tertiary N-phenylpropargyl amines can be involved in this reaction. A possible mechanism includes the copper-catalyzed oxidative dehydrogenation of propargylamines in air followed by disproportionation of elemental sulfur in the presence of K 3 PO 4 with release of the S 2 dianion and the SH anion. Simultaneous nucleophilic additions of the S 2 dianion to the carbon-carbon triple bond followed by copper-catalyzed dehydrogenative oxidation and hydrolysis resulted in 1,2-dithiol-3-one. Finally, nucleophilic addition of the SH anion to 1,2-dithiol-3-one followed by elimination gave the target 1,2-dithiole-3-thione.  The general strategy for the synthesis of 1,2-dithioles from isopropyl or isopropenyl derivatives is to add two sulfur atoms from elemental sulfur. Recently, however, disulfur dichloride has successfully replaced this reagent for tertiary isopropylamines. The main feature of this reagent is that it has diverse reactivity, which determines both its beneficial and adverse properties. Disulfur dichloride exhibits the properties of a sulfurating, chlorinating, oxidizing, and even dehydrating agent [50]. The most important property of disulfur dichloride is its ability to cause cyclization of various organic molecules into sulfur-containing heterocycles, in particular 1,2-dithiole-3-thiones [51][52][53].
The concept of synthesizing 1,2-dithioles from tertiary isopropylamines and disulfur dichloride was discovered and developed by the author of this review in collaboration with Professor Rees (Imperial College London, UK) in the late 90s of the past century and at the beginning of this century. It was found that N-ethyldiisopropylamine (Hünig's base), which was previously used in reactions with disulfur dichloride as an "inert" base, can react with S 2 Cl 2 and 1,4-diazabicyclooctane (DABCO) to give a completely unexpected new polysulfur-containing heterocyclic system, namely, bis [1,2]dithiolo [1,4]thiazine 8 [54]. In this one-pot reaction, the 14 isopropyl C-H bonds of the Hünig base were replaced by 10 C-S and two C= C bonds, while the ethyl group was left intact (Scheme 17).  [1,4]thiazin-3-one 9 was obtained by the reaction of Hünig's base with disulfur dichloride with addition of an oxygen donor, namely cyclopentylacetic acid, at the last stage of the reaction (Scheme 18) [55]. By extending the conditions found to other substituted diisopropylamines, a number of bis(dithiolo)thiazines were obtained, including nitrogen-unsubstituted representatives of these heterocycles [56][57][58]. In all the reactions described above in this section, both isopropyl groups in the Nalkyldiisopropylamines were converted to 1,2-dithiole rings. It was shown later that the reaction could be stopped at the stage of the formation of monocyclic 1,2-dithioles, and the main condition for the successful synthesis of monodithioles is that the conversion should be performed at low temperature [61]. Treatment of N-alkyldiisopropylamines and S 2 Cl 2 in chloroform at 0 • C in the absence of another base resulted in monocyclic 1,2-dithiole-3-thiones 13 and 14; in all cases, the 5-mercapto derivatives 13 were the main products (Scheme 21). Unexpected results were obtained in the reaction of two other substituted diisopropylamines with disulfur dichloride [62]. Dithiolothiazine 15 was isolated instead of the expected mercaptodithiolethiones 16 (Scheme 22). The authors believe that in the course of the reaction, thiones 16 were also formed as intermediates and then converted into bicyclic structure 15 after elimination of HCl or phthalimide, respectively. Treatment of N-(2-chloroethyl) diisopropylamine with disulfur dichloride followed by addition of phosphorus pentasulfide resulted in dithiolothiazine 17 [63]. The formation of this product can be explained by the fact that, in the presence of P 4 S 10 , salt 18 gives another salt 19, which undergoes cyclization to thiazine ring 20. The conversion of salt 20 into thiazine 17 apparently occurs due to the action of the same P 4 S 10 as a sulfurating agent (Scheme 23). 5-Chloro-1,2-dithiole-3-thiones 21 were obtained by the reaction of N-(2-phthalimidoethyl)-N-alkylisopropylamines with a mixture of disulfur dichloride and DABCO followed by the action of triethylamine [64]. The unexpected stability of thiones 21 was explained by the dipole-dipole interaction between an electron-donor 1,2-dithiole-3-thione ring and an electron-withdrawing phthalimide group (Scheme 24). Treatment of 3,4-bis(iso-propylamino)-1,2,5-oxadiazole 22 with disulfur dichloride in DMF at 100-105 • C gave a product containing one isopropyl group, dithioloxadiazolopyrazinethione 23, whose structure was confirmed by X-ray diffraction analysis [65]. The formation of this product was explained by the conversion of the N-isopropyl group to the 3-chlorodithiolium salt 24 in accordance with the mechanism described earlier [55]. The latter compound evolved hydrogen chloride to form the pyrazine ring (Scheme 25). Obviously, the formation of the dithiolethione and pyrazine rings in compound 23 deactivates the second isopropyl group, which does not undergo further conversion. The reaction of diisopropyl sulfide with disulfur dichloride and DABCO resulted in 1,2-dithiole-3-thiones 25 and 26 [66]. Apparently, the formation of the dithiole ring is similar to its production from diisopropylamines. However, in the case of diisopropyl sulfide, only one isopropyl group reacted, whereas the second one was apparently deactivated by incorporation of a dithiolethione moiety at the sulfur atom (Scheme 26).
It was shown above that N-isopropyl groups could be converted to N-(1,2-dithiole-3-thione) moieties. Nitrogen-containing heterocycles with methyl and C-H groups at the ortho-position, for example, readily available 2-and 3-methylindoles, are structurally similar to the N-isopropyl group and can be considered as starting materials for the synthesis of dithioloindoles.
Treatment of N-methyl-2-methylindole with a fivefold excess of disalt 27 obtained from disulfur dichloride (one equivalent) and DABCO (two equivalents) in chloroform at room temperature [67] followed by addition of triethylamine gave fused dithioloindole 28 (R = Me) in high to moderate yields [68]. Later, this reaction was extended to other N-substituted 2-methylindoles [69]. Fused dithioloindoles 28 were obtained in good yields (Scheme 27). N-Acetyland N-benzoyl-2-methylindoles did not react with S 2 Cl 2 even under more drastic conditions; the starting indoles were isolated from the reaction mixtures in high yields. It is obvious that electron-withdrawing substituents at the nitrogen atom of the indole ring (acetyl and benzoyl groups) suppress the reaction with electrophilic disulfur dichloride. It was found that the 3-methyl group in 1,3-dimethylindole does not react with S 2 Cl 2 and its mixtures, in contrast to the 2-methyl group in 1,2-dimethylindole. The high reactivity of the 2-methyl group can be explained by the low acidity of the 2methyl hydrogens. The most plausible mechanism for the formation of dithioloindoles is apparently similar to the mechanism of the formation of a 1,2-dithiole-3-thione moiety from tertiary N-isopropylamines and involves the addition of a S 2 Cl 2 molecule followed by the formation of a 1,2-dithiole ring and then oxidation and chlorination to a 3-chlorodithiolium salt. Sulfur nucleophiles formed from sulfur and triethylamine are likely to produce a thione group.

Scheme 27. Synthesis of dithioloindoles 28.
Interestingly, almost simultaneously with this work, a paper appeared describing the synthesis of 1,2-dithiole-3-thione annulated with a phosphole sulfide ring 30 [70] from the corresponding heterocycle 29, in which the methyl and C-H groups are at ortho-positions to each other (Scheme 28). A successful reaction with S 2 Cl 2 requires activation with a base (in this case, sodium hexamethyldisilazide, (Me 3 Si) 2 NNa); the yield of fused dithiolethione 30 was as small as 10%. Pentathiepinopyrroles 31 reacted with salt 32 obtained from disulfur dichloride and DABCO to give bis(1,2-dithiolo)pyrroles 10 in high yields [71]. Pentathiepins usually do not react with the S 2 Cl 2 -DABCO system at room temperature; therefore, it was assumed that salt 32 reacted with methyl groups as an electrophilic reagent to afford bis(1,2-dithiolo)pyrroles 10 in a complex cascade transformation (Scheme 29).

Miscellaneous Syntheses of 3H-1,2-dithiole-3-thiones
A new procedure was suggested to synthesize 1,2-dithiole-3-thiones from cyclopropenthione derivatives and elemental sulfur in the presence of potassium fluoride in DMF in an air or oxygen atmosphere [72]. The features of the reaction include a high efficiency and good regioselectivity with respect to a wide range of cyclopropenthione derivatives (Scheme 30). The suggested mechanism for this [3+2] cycloaddition includes attack of elemental sulfur on the positively charged carbon atom of the cyclopropenthione derivative followed by release of S 6 with a further ring-opening/cyclization sequence to give dithiolethiones. Scheme 30. Synthesis of 1,2-dithiole-3-thiones from cyclopropenthione derivatives.
Substituted 3H-benzo [1,2]dithiole-3-thiones 33 can be prepared by treatment of 2bromobenzaldehydes with potassium sulfide in DMF [73]. This method is superior to those previously described for benzodithiolethiones in terms of the number of steps and efficiency (Scheme 31). A possible mechanism of this reaction involves aromatic substitution of 2bromobenzaldehyde with potassium sulfide followed by the reaction with elemental sulfur formed by oxidation of potassium sulfide with atmospheric oxygen and the subsequent Willgerodt-Kindlertype reaction, which affords the final benzodithiolethione. Two procedures have been suggested for the synthesis of the parent 3H-1,2-dithiole-3thione (1,2-Trithione). Treatment of commercially available malonodialdehyde dimethylacetal by heating at 130 • C with a mixture of elemental sulfur and P 4 S 10 in pyridine gave 3H-1,2-dithiole-3-thione in a good yield [74]. Thermolysis of dipropyl polysulfides (n-Pr) 2 S x (x = 3, 3.5) at 350 • C gave 1,2-dithiole-3-thione in moderate yield [75]; the process was accompanied by the evolution of gaseous products such as hydrogen sulfide, propylene and hydrogen (Scheme 32). Scheme 32. Synthesis of the parent 3H-1,2-dithiole-3-thione.

Reactions of 3H-1,2-dithiole-3-thiones
There are several typical reactions of 1,2-dithiole-3-thiones that have been studied for decades: 1,3-dipolar cycloaddition to alkynes, isonitriles, nitrilimines, various transformation of thione group, as well as some new transformations that have been discovered recently: recyclization to other heterocycles, insertion of several fragments into an S-S bond, and some others.
As a rule, the reaction of non-fused dithiolethiones is stopped at the stage of addition of one mole of an alkyne (Scheme 34). Usually, one equivalent of an alkyne should be added to the reaction mixture to obtain 1,3-dithioles 34, and the conversion is carried out at room temperature or even below it [37,76,77], but in some cases refluxing with an excess of an alkyne in xylene or benzene was employed [64,66,78,79]. The yields of 1,3-dithioles can vary widely from 20% to the quantitative yield. It is noteworthy that in the case of 5-chlorosubstituted dithiolethiones, rare aliphatic compounds with a usually unstable thioacyl chloride group are formed [80]. The stability of compound 35 is due to the intramolecular interaction between the thiocarbonyl group and the heterocyclic sulfur atom that can reduce the electrophilicity of the thiocarbonyl group (Scheme 35). In the case of compound 35, this was confirmed using X-ray diffraction analysis, which showed the planarity of the quasibicyclic part of the molecule with an S...S distance of 2.91 Å. It is in the range between the length of the usual S-S bond (2.05 Å) and the sum of van der Waals radii for these atoms (3.68 Å). In light of the above, rather an unexpected result was obtained in the reaction of 5-methyl-3H-1,2-dithiole-3-thione with DMAD. When these reagents were refluxed in chloroform for 5 h, only the addition product of two DMAD molecules, thiopyrane 36, was isolated in 78% yield [81]. However, it should be noted that the authors did not attempt to obtain the intermediate 1,3-dithiole 37 (Scheme 36). Scheme 36. Synthesis of thiopyrane 36.
As a rule, 1,2-dithiole-3-thiones fused with non-aromatic and heteroaromatic rings sequentially add first one and then the second mole of an activated alkyne. Moreover, it was often difficult to stop the reaction at the first stage, and as a result, 1,3-dithioles were isolated in low yields. In fact, the reactions of [l,2]dithiolo [3,4-c]quinoline thiones 38 and 39 gave 1,3dithioles 40 and 41 at room temperature in chloroform [82,83] or dimethylformamide [84], while the addition of the second mole of DMAD was performed by refluxing in toluene (Scheme 37). Similar results were obtained in the reaction of bis-dithiolothiazines with DMAD and dibenzoylacetylene [85,86]. Short-term refluxing (10-45 min) of monothiones 44 or bisthiones 45 with one equivalent of an alkyne in benzene gave mono-46 and bis(1,3-dithioles) 47 in moderate to high yields (Scheme 38). The use of scandium triflate as a catalyst increased the yields of 1,3-dithioles significantly, up to 60-80%. If excess alkyne was added to monothiones 44 or bis-thiones 45 in refluxing toluene or benzene, dithiolopyranes 48 and 49 were formed. It is noteworthy that the yields of 1,3-dithioles and thiopyranes are nearly the same, which indicates that the second alkyne molecule is added quantitatively. Interesting results were obtained in a study of the reaction of dithioloindoles 28 and 50 with DMAD [68]. In the reaction of dithiole 28 with DMAD, the first molecule was added somewhat more slowly than the second one, and in all cases, mixtures of monoand bis-products formed (Scheme 39). The highest yields of 1,3-dithioles 51 (25-35%) were obtained in the reaction with one equivalent of DMAD in benzene at room temperature for three days. Monoadducts 51 reacted with one mole of DMAD in benzene under reflux to form bis-adducts 52 in a quantitative yield in a few minutes. The reaction of thione 50 with excess DMAD in benzene under reflux conditions gave only monoproduct 53 in a low yield (18%). The expected bis-adduct 54 was not detected in the reaction medium; instead of this product, ketone 55 was isolated in 23% yield. The formation of this product was unexpected. In an attempt to explain this result, it was found that it was formed in 65% yield from thione 53 on treatment with DMAD. Thus, thione 53, which is a regioisomer of thione 51, in contrast to the latter, does not react with DMAD as with a dienophile. Obviously, the reason for this lies in the different reactivity of the thiono groups in these compounds. The thiono group in 53 is essentially a thioamide group in nature and is therefore not involved in 1,3-dipolar cycloaddition reactions.
In the case of monothioxo 11 and bis-thioxo 10 bis [1,2]dithiolopyrroles, the reaction occurs with two moles of an activated alkyne per thiono group and ends with the formation of spiro-1,3-dithiolopyrans 56 and 57 [85,86]. Only in one case, in the reaction of thione 11 with one equivalent of DMAD in the presence of scandium triflate (Sc(OTf) 3 ), the addition product of one alkyne molecule 58 could be isolated in a low yield. The latter was found to be unstable and decomposed back to thione 11 on storage (Scheme 40). The reaction of 58 with a second equivalent of DMAD readily gave spiro-1,3-dithiolopyrane 56 in quantitative yield. The authors explain the instability of product 58 by the loss of aromaticity of the pyrrole ring, which can be restored upon reaction with the second dienophile molecule or upon its conversion back to the initial bis(dithiolo)pyrrole 11 [85]. As expected, the reaction of thione 59 with DMAD gave 1,3-dithiole 60 at room temperature [40]. Irradiation of a mixture of 1,3-dithiole 60 and DMAD with a 500-volt tungsten lamp for 0.5 h resulted in thiopyrane 61 in 75% yield. However, this substance turned out to be unstable to moisture contained in silica gel and, after filtration through its layer, it is converted to hydroxy adduct 62 in a yield of 64%. It is noteworthy that all the reactions can be carried out in one flask from thione 59 without isolating the intermediate products.
The 1,3-dipolar cycloaddition to unsymmetrical alkynes has been studied less thoroughly. There are several reasons for this fact. The incorporation of hydrogen atoms or a phenyl group into an alkyne molecule instead of strong electron-deficient substituents, such as ester (CO 2 Alk), benzoyl (C(O)Ph), or nitrile (CN) groups, significantly reduces the reactivity of alkynes in these processes. In addition, reactions with unsymmetrical alkynes result in mixtures of regioisomers that are difficult or almost impossible to separate, which reduces the synthetic value of this method.
Shikhaliev et al. studied the cycloaddition of ethyl propiolate to 4,5-dihydro-4,4dimethyl- [1,2]dithiolo [5,4-c]quinoline-1-thiones 15 and showed that, depending on the conditions used (solvent and temperature), the reaction can occur quite selectively both with one or two alkyne molecules and with cleavage of the thioketone bond as [2+2] cycloaddition followed by recyclization (Scheme 42). For example, refluxing equimolar amounts of reagents in chloroform gave 1,3-dithioles 63. Treatment of ethyl propiolate with thiones 15 at a higher temperature (in boiling xylene) occurs with cleavage of the thioketone bond followed by recyclization to trithiapentalenes 64. The reaction in toluene with two moles of ethyl propiolate afforded 1:2 adducts 65 in high yields. In all cases, several sets of signals from carbethoxy groups and quasi-aromatic protons were observed in the 1 H NMR spectra, which indicates that these reactions are not regioselective [87]. The possibility of benzyne addition to dithiolethione 9 was studied [58]. It was found that the majority of the known methods for generating benzyne were unsuitable for cycloaddition in this case (Scheme 45). The only successful method for synthesizing the cycloaddition product 72 in a high yield from benzyne was implemented using one of the mildest methods for benzyne generation from iodonium salt 71. Scheme 45. Reaction of dithiolethione 9 with benzyne.
Treatment of bisdithiolothiazines 44 and 45 with commercial maleimides in the presence of scandium triflate, a catalyst which was very efficient in the 1,3-cycloaddition of polyheterocyclic dithiolethiones and activated alkynes [58,88], gave the corresponding mono-74 and bis-adducts 75 with two or four chiral centers. The 1 H NMR spectra of the latter were quite difficult to interpret (Scheme 47) [90].

Reactions with Nitrilimines
The reaction of nitrilimines with 1,2-dithiole-3-thiones occurs as 1,3-dipolar cycloaddition at the thiono group and is accompanied by spontaneous opening of the dithiole ring with extrusion of the sulfur atom and formation of a 1,3,4-thiadiazole ring.

Recyclization Reactions
Various monocyclic and fused 3H-1,2-dithiole-3-thiones can undergo a carbon-nitrogen or carbon-carbon bond insertion reaction, usually with extrusion of a sulfur atom. Neat treatment of an excess 3,4-dihydropyrrolo[1,2-a]pyrazine 86 with 3H-benzo[c] [1,2]dithiole-3-thione at room temperature gave pyrazino [2,1-b] [1,3]thiazine 87 in 64% yield [95,96]. Although this reaction requires a large excess of pyrazine 86, unreacted dihydropyrrolopyrazine 86 was fully recovered from the reaction mixture. All attempts to improve the reaction procedure, such as heating equimolar quantities of both reagents under reflux conditions in various solvents (benzene, MeCN, pyridine or in DMSO, sulfolane or DMF at 95 • C) or treatment of a neat mixture of these reagents with Et 3 N under reflux for two days, failed. The scope of this one-pot reaction was studied: the yields of 1,3-thiazine-4-thiones 87 strongly depended on the structure of fused and monocyclic 1,2-dithiole-3-thiones (Scheme 54). The most reactive 1,2-dithiole-3-thiones fused with electron-withdrawing cycles (pyridine and dihydroindenone) reacted relatively quickly, while monocyclic ones required prolonged stirring and failed to completely consume the dithiolethiones even in 60 days. Finally, the S2 atom in both monocyclic and fused 1,2-dithioles is selectively replaced by the aminomethylene group to afford fused rigid six-membered 1,3-thiazines 87. Surprisingly, the thiopyranthione ring is formed as a result of the reactions of 1,2dithiole-3-thiones with completely different reagents, namely, DMAD and sodium sulfide. Treatment of 4,5-dichloro-3H-1,2-dithiole-3-thione 78 (R = Cl) with excess DMAD in xylene, first at room temperature and then under reflux conditions, gave thienothiopyranethione isomers 91 and 92 in moderate yields [80]. Thus, the reaction occurs in a completely different way than in the case of 1,2-dithiole-3-thiones that do not contain two chlorine atoms as substituents (see Section 2.1): when two DMAD molecules are added, two chlorine atoms are removed (Scheme 56). As expected, the first step involved the addition of the first DMAD molecule to give thioacyl chloride 79. The latter reacts with the second DMAD molecule with a rearrangement to afford thienothiopyranethione isomers 91 and 92. To study the mechanism of formation of products 91 and 92, the behavior of three intermediate 1,3-dithiols 79 with three alkynes, i.e., DMAD, acetylene dicarboxylic acid diethyl ester (DEAD), and dibenzoylacetylene (DBA), was studied. In each case, a pair of isomeric thienothiopyranethions 91 and 92 was isolated, and it was unexpectedly found by means of XRD that in all cases the alkyne moiety of 79 appeared in the thiophene ring, while the second alkyne molecule was found in thiopyranes 91 and 92.
The possible pathways for the formation of thiopyranes 91 and 92 were suggested. The authors believe that the main reason for these rearrangements lies in the presence of an intramolecular S...S bond in molecule 62 (proved by X-ray diffraction analysis), which can reduce the ability of these compounds to undergo Diels-Alder cycloaddition and, at high temperatures, leads to a chain of reactions involving the opening and closure of various heterocyclic rings. The formation of the final heteroaromatic products 91 and 92 can occur upon elimination of a chlorine molecule from the dichloro adducts. The presence of a chlorine molecule in the reaction mixtures was proved by isolation of the same xylene chlorination products, like in the case where xylene was refluxed with chlorine.
Yet another example of the formation of a thiopyrane ring from 1,2-dithiole-3-thione was observed in the reduction of 4-fluoro-5-(1,1,2,2-tetrafluoroethyl)-1,2-dithiole-3-thione 93 with sodium sulfide [98]. It was found that refluxing dithiolethione 93 with excess sodium sulfide gave thiopyranthione 94 (Scheme 57). Trithiapentalene 95 was isolated by using an equimolar ratio of the reagents under the same conditions. The formation of the trithiapentalene system was explained as a sequential process of reduction and substitution of fluorine atoms under the action of a sulfide anion followed by its addition and elimination of the vinyl sulfur atom, while the formation of the thiopyrane system was followed by a rearrangement of the trithiapentalene system.

Scheme 57. Synthesis of thiopyranthione 94.
A number of 1,2-dithiole-3-thiones, both monocyclic and fused 11, were studied in the reaction with Fischer's carbene complex 96 [99]. Insertion of a carbene moiety into the S...S bond resulted in 1,3-dithiine-4-thiones 97 and 98, which were isolated after treatment of intermediate complexes 99 and 100 with methanol (Scheme 58). It is noteworthy that ketone 101 does not react with the Fischer carbene complex 96, thus the presence of a thiocarbonyl group is the main condition for incorporation into the 1,2-dithiole ring. This is confirmed by the fact that the reaction of tricyclic compound 11 containing 1,2-dithiole-3thione and 1,2-dithiol-3-one rings in its molecule with Fischer's carbene complex 96 gave only a product of insertion in the 1,2-dithiole-3-thione ring 98. The authors suggest that this selectivity indicates that the reaction begins with the attack of the nucleophilic thiocarbonyl group on the electrophilic carbenium atom of the Fischer carbene complex. Interestingly, in the first report on the reaction of 1,2-dithiole-3-thiones with Fischer carbene complexes, the authors argued that the incorporation of the carbene ligand occurs via the C3-C4 bond of the dithiole ring [100]. In a subsequent paper [99], an X-ray diffraction analysis of the compounds obtained was carried out and the initial data were corrected. The possibility of insertion of a carbon-containing particle was also demonstrated in the reaction of 1,2-dithiole-3-thione 102 with phosphonium ylides [101]. After treatment of thione 102 with phosphonium salts 103 in the presence of lithium hydroxide in DMF, 1,3-dithiine 4-thione 104 was isolated as the main product (Scheme 59). Egyptian authors have shown that in the reaction of 4-phenyl-1,2-dithiole-3-thione with nitriles containing a reactive methylene group and with α,β-unsaturated nitriles, the sulfur atom is replaced by a C-C bond, while the carbon atom of the nitrile group and the adjacent carbon atom are included in the new cycle [102]. Thus, the reaction of 4-phenyl-1,2-dithiole-3-thione with 2-cyanomethyl-benzothiazole and -benzimidazole 105 in the presence of triethylamine gave products that the authors concluded to have the structure of imino-2H-thiopyran-2-thiones 106 (Scheme 60).
At the same time, in the case of the reaction of acetonitriles 107, which are structurally similar to compounds 88 under similar conditions, the amide group is involved in the reaction rather than the nitrile group, as might be expected from the previous scheme [102]. As a result, 2H-thiopyran-2-thiones 108 were isolated in high yields (Scheme 61). The reaction with conjugated nitriles 113 also involved the nitrile group and resulted in 2H-thiopyran-2-thiones 114 [102,104]. The reaction conditions are the same as in all previous transformations, i.e., refluxing in ethyl alcohol in the presence of a base (piperidine or triethylamine) (Scheme 64). If an acetamide group is present in a conjugated nitrile, then it is dehydrated into a nitrile group [102]. In all the cases described in this section, it is assumed that the cyclic sulfur atom at position 1 undergoes replacement. Unfortunately, the structure of the compounds synthesized is proven only by elemental analysis, IR and NMR spectra, which does not allow their structures to be identified unambiguously. The other drawback of these studies is that the fate of the sulfur atom was not clarified in any of the cases.

Oxidation of 1,2-dithiole-3-thiones
Mercury acetate, a readily available and inexpensive reagent, is the most commonly used oxidant for 1,2-dithiole-3-thiones; chloroform, acetic acid or their mixtures are used as solvents. It follows from an analysis of literature data that the solubility of both 1,2dithiole-3-thione and mercury acetate can be the main criterion for the choice of the solvents. Heating of monocyclic 1,2-dithiole-3-thiones in acetic acid was used most often [110][111][112][113], however, the yields can vary widely from 18 to 82%, and no dependence of the yields on the nature of substituents at positions 4 and 5 of the heterocycle was found (Scheme 69). The reaction of 1,2-dithiole-3-thiones with nitrile oxides is yet another useful procedure. Nitrile oxides are unstable compounds that can readily dimerize to 1,2,5-oxadiazole 1-oxides (furoxans); therefore, they are prepared in situ by the reaction of hydroxamic acid chlorides with triethylamine (Scheme 70). Commercial hydroxamic acid chloride, viz., ethyl chloroximidoacetate [55], and phenylhydroxamic acid chloride that is easy to synthesize [114,115] were employed. A comparison of two reagents, mercury acetate and nitrile oxide, was carried out in Ref. [55]; it was found that in all the cases studied, the yields of dithiolethiones were significantly higher if the second method was used.
Mercaptodithiolethiones 13 were brought into the reaction with a mixture of S 2 Cl 2 and DABCO under the conditions for the formation of tricyclic bis-dithiolothiazines 8 and 9 from substituted diisopropylamines [55]. However, contrary to expectations, 5chlordithiole-3-ones 122 formed in high yields in all the cases (Scheme 71) [62]. It was assumed that the most likely precursor of 122 was dichlorodithiolium salts 123, which reacted with HCO 2 H to give chloroketone 122, as described previously [61]. Apparently, the formation of this salt occurred as a result of a two-fold attack by an electrophilic S 2 Cl 2 on the thione group of 13. Scheme 71. Reaction of mercaptodithiolethiones with S 2 Cl 2 and HCO 2 H.

Synthesis of 1,2-dithiolium Salts
There are two main methods for the formation of 1,2-dithiolium salts from 1,2-dithiole-3-thiones: i, alkylation with alkyl halides; ii, chlorination of 1,2-dithiole-3-thiones. Monocyclic 1,2-dithiole-3-thiones reacted with alkyl and benzyl iodides at room temperature (Scheme 72). The treatment with methyl iodide was carried out in acetone [114,116], in benzene [117] or in DMF for 1,2-dithiole-3-thiones containing ferrocenyl [114], aryl substituents [116,117], and functional (nitrile, ester and carboxamide) groups [118]. The yields of 1,2-dithiolium salts were usually high (70-90%), though they were low in some cases (down to 17%). Bromo derivatives activated by an α-carbonyl group were employed for the synthesis of 1,2-dithiolium salts less frequently [119]. The yields of salts 124 were as low as 27-47% (Scheme 73). The reaction of 5-(hydroxylaminoalkyl)-1,2-dithiole-3-thiones 125 with methyl iodide in water in the presence of sodium hydroxide involved, along with the alkylation of the exocyclic sulfur atom, also a rearrangement of bonds in the 1,2-dithiole ring and oxime group. Nitroso derivatives 126 were formed in quantitative yields (Scheme 74). Compounds 126 can be considered as heteropentalenes due to the strong interaction of the oxygen atom of the nitroso group and the sulfur atom of the cycle [120]. Reactions of fluorinated 1,2-dithiole-3-thiones with chlorinating agents (chlorine or sulfuryl chloride) resulted in the chlorination of exocyclic sulfur atom 127 [111,121]. These compounds were typically used in situ in further reactions. However, in one case, product 127 was isolated and characterized (Scheme 75). If an excess of the chlorinating agent (SO 2 Cl 2 ) was used in the reaction with fluorinated 1,2-dithiole-3-thione, the thione group was replaced by two chlorine atoms and the double bond of the 1,2-dithiole ring was also halogenated [111]. The 1,2-dithiolium salts reacted in situ with primary amines or their trimethylsilyl derivatives to give 1,2-dithiole-3-imines 129 in good yields [121]. The reaction of trimethylsilyldiethylamine with salt 128 gave the dithioloiminium salt 130 in an even higher yield (Scheme 76). The authors suggested that its formation occurred through the intermediate salt 131 from which a sulfur atom was extruded.

Reaction of 1,2-dithiole-3-thiones with N-Nucleophiles
The reaction of 1,2-dithiole-3-thiones with amines has been studied for a long time. It was reported that the imine function could replace both endocyclic (in the first and second positions) and exocyclic sulfur atoms. However, this reaction has not yet been clarified. In fact, 1,2-dithiole-3-thiones fused with aromatic and heteroaromatic rings were studied in reactions with aliphatic amines in ethanol (Scheme 77) [122,123]. In both cases, the authors suggested that the reactions resulted in inseparable mixtures of regioisomers 132 and 133, in which the exocyclic sulfur atom at position 2 and the endocyclic sulfur atom, respectively, were replaced. The yields were moderate in both cases. The formation of 1,2-dithiole-3-imines from 1,2-dithiole-3-thiones can occur in the reactions of the latter with chloramines B and T. It was found [60] that the reaction of tricyclic dithiolethiones 9 and 8 with these reagents in benzene in the presence of acetic acid gave mono-134 and bis-imines 135 in moderate yields (Scheme 78). Replacement of acetic acid with a Lewis acid (scandium triflate) significantly increased the reaction rate and the yields of the final products. For example, the reaction of 9 with chloramines B and T in the presence of scandium triflate in DCM at room temperature for 5-15 min afforded imines 135 in 73 and 89% yields, respectively.
Organic azides are yet another reagents that can convert 1,2-dithiole-3-thiones to 1,2-dithiole-3-imines. It was found that ethoxycarbonyl azide gave stable imines in the reaction with fused 1,2-dithiole-3-thiones 9-11 (Scheme 79). The reaction was carried out in refluxing toluene, and the yields of imines 136-138 varied greatly from low to almost quantitative values [92]. The mechanism of formation of these imines can be represented as a 1,3-dipolar cycloaddition of an azide to a thione group, followed by the extrusion of a nitrogen molecule to give a thiaziridine derivative, which in turn extruded a sulfur atom to give the final imines 136-138. The oximine group can be easily incorporated into the 1,2-dithiole ring by the reaction of 4,5-diaryl-3H-1,2-dithiole-3-thiones with hydroxylamine or its O-methyl derivative in refluxing ethanol (Scheme 80) [29].

Miscellaneous Reactions
Treatment of 4-cyano-5-aryl-3H-1,2-dithiole-3-thione 145 with trialkyl phosphites [126] gave a number of products: two of them (146 and 147) are products of thione group replacement for a phosphorus-containing moiety, and the third one, 148, is the product of 1,2-dithiole dimerization (Scheme 85). The authors provided complex mechanisms of their formation but gave no serious evidence of the structure of these products. Treatment of Oltipraz or its derivatives with sodium methoxide in MeOH afforded pyrrolo[1,2-a]pyrazines 149 [30,127]. Methyl iodide was added at the last reaction stage to stabilize the thiolo groups, which formed at the first step, to methylthio derivatives (Scheme 86). Thiomethoxide was assumed to attack C-4 instead of S-2 and the subsequent ring closure resulted in the final bicycle 149. These results are of interest in biological context as they may contribute to the understanding of the pharmacological activity of Oltipraz. Scheme 86. Reaction of Oltipraz and its derivatives with sodium methoxide.