Exploiting amphiphilicity: facile metal free access to thianthrenes and related sulphur heterocycles

In the last decades sulphur-containing molecules have received great attention because of their interesting biological properties and their unique application in material science. For that purpose, the development of new methodologies dealing with the formation of carbon–sulphur bonds has become a major topic in modern organic synthesis. Traditional methods which take advantage of the high nucleophilicity of sulphur require harsh reaction conditions to form arene–sulphur bonds. Therefore, elevated temperatures, strong bases or a specific substitution pattern at the arene are needed making them unattractive for numerous target molecules. These drawbacks could be bypassed utilising metal catalysed cross-coupling reactions for C–S bond formation. Nevertheless, applications in material science require highly pure compounds without any extraneous metal impurities. Thus, transition metal free protocols for the formation of C–S bonds under mild reaction conditions are of considerable interest. Regarding the reaction properties of thiophenols, sulphur reacts as a nucleophile. However, its philicity can be reversed by converting thiophenol into the corresponding sulfenyl chloride or thiocyanate. In this shape, sulphur acts as electrophile suitable for substitution by nucleophiles (e.g. lithium or Grignard reagents). For the facile synthesis of heterocycles containing two sulphur atoms, 1,2-thiophenol derivatives equipped with both abilities are of utmost importance (Scheme 1a). This means one sulphur atom should act as nucleophile, the other one as electrophile. 2-Thiocyanatobenzenethiol (1a0) which exists in its closed form 1a was chosen as target substrate. Providing the required abilities easily visualised by its open form 1a00, compound 1a should be able to react with other easily polarisable or polarised substrates such as arynes or alkynes substituted with electron-withdrawing (EWG) groups. As products, the corresponding dithiaheterocycles 3aa and 5, respectively, should be formed (Scheme 1b). At the beginning of our investigations, we intended to establish a fast and efficient access to key compound 1a since the methods described in the literature proved to be tedious. We discovered, when treating aromatic 1,2-dithiocyanatobenzene 6a with PPh3 in the presence of base in acetonitrile, 1a is formed in up to 91% yield within 1 h at room temperature (Scheme 2a). With compound 1a in hand, we proved the amphiphilic behaviour of the two sulphur atoms. Based on our previous considerations, we chose a common aryne precursor for the desired metal free transformation which would provide a novel entry to the thianthrene scaffold. To our delight, common Scheme 1 (a) Reaction mode of mononitrile-substituted 1,2-dithiophenol. (b) Possible reaction partners and desired products.

In the last decades sulphur-containing molecules have received great attention because of their interesting biological properties 1 and their unique application in material science. 2 For that purpose, the development of new methodologies dealing with the formation of carbon-sulphur bonds has become a major topic in modern organic synthesis. 3 Traditional methods which take advantage of the high nucleophilicity of sulphur require harsh reaction conditions to form arene-sulphur bonds. Therefore, elevated temperatures, strong bases or a specific substitution pattern at the arene are needed making them unattractive for numerous target molecules. 4 These drawbacks could be bypassed utilising metal catalysed cross-coupling reactions for C-S bond formation. 5 Nevertheless, applications in material science require highly pure compounds without any extraneous metal impurities. Thus, transition metal free protocols for the formation of C-S bonds under mild reaction conditions are of considerable interest. 6 Regarding the reaction properties of thiophenols, sulphur reacts as a nucleophile. However, its philicity can be reversed by converting thiophenol into the corresponding sulfenyl chloride or thiocyanate. In this shape, sulphur acts as electrophile suitable for substitution by nucleophiles (e.g. lithium or Grignard reagents). 7 For the facile synthesis of heterocycles containing two sulphur atoms, 1,2-thiophenol derivatives equipped with both abilities are of utmost importance (Scheme 1a). This means one sulphur atom should act as nucleophile, the other one as electrophile. 2-Thiocyanatobenzenethiol (1a 0 ) which exists in its closed form 1a was chosen as target substrate. 8 Providing the required abilities easily visualised by its open form 1a 00 , compound 1a should be able to react with other easily polarisable or polarised substrates such as arynes 9 or alkynes substituted with electron-withdrawing (EWG) groups. 10 As products, the corresponding dithiaheterocycles 3aa and 5, respectively, should be formed (Scheme 1b).
At the beginning of our investigations, we intended to establish a fast and efficient access to key compound 1a since the methods described in the literature proved to be tedious. 8 We discovered, when treating aromatic 1,2-dithiocyanatobenzene 6a with PPh 3 in the presence of base in acetonitrile, 1a is formed in up to 91% yield within 1 h at room temperature (Scheme 2a). With compound 1a in hand, we proved the amphiphilic behaviour of the two sulphur atoms. Based on our previous considerations, we chose a common aryne precursor for the desired metal free transformation which would provide a novel entry to the thianthrene scaffold. 11 To our delight, common conditions using KF and 18-crown-6 in acetonitrile at ambient temperature yielded the desired thianthrene 3aa in excellent 95% yield (Scheme 2b).
Exposition of 1a to various aryne precursors under the abovementioned reaction conditions yielded the corresponding thianthrenes (Table 1). Alkyl-substituted arynes and such with extended p-systems were successfully converted to their thianthrene counterparts 3ab-3af in 58-87% yield. Chloro-, fluoro-, and bromo-substituted thianthrenes 3ag, 3ah, and 3ai were obtained in yields ranging from 44 to 74%. In the case of the dibromo derivative 3ai higher loadings of aryne precursor were required. Thianthrenes equipped with one or two methoxy substituents 3aj and 3ak were accessed in 64% and 96% yield, respectively. Furthermore, also a pyridine-based aryne precursor was able to undergo the transformation to azathianthrene 3al in 75% yield.
Similarly, variations with respect to the dithioloimine bearing core are possible (Table 2). Methyl-substituted 1b in combination with the unfunctionalised aryne precursor was exposed to the reaction conditions yielding 3ba in 71%. Naphthyl-based 3be, difluoro-3bh and dimethyoxy-substituted systems 3bk were obtained in yields ranging from 55 to 70%. Because of their high electronegativity the latter two substituents render the important in-plane p orbital of the aryne highly electrondeficient. Further, benzodithioloimines containing pyrazine or thiadiazole heterocyclic cores were also applied. Pyrazine derivative 3ca could be obtained in 69% yield, whereas the formation of 3ca stayed out.
Finally, 1b was exposed to unsymmetrical aryne precursors substituted with a methyl or a methoxy group. As result, inseparable mixtures of 3bc/3bc 0 (64%, ratio of 1 : 1) and 3bj/3bj 0 (79%, ratio of 2 : 1) were obtained, respectively. This observation demonstrates that even the methoxy-substituted aryne, known for its high distortion and hence its high regioselectivity in aryne chemistry, does not achieve a satisfying ratio of regioisomers. 12 In addition, we also tried a one-step procedure applying 1,2-dithiocyanatobenzene 6a by addition of PPh 3 to the aryne reaction. Unfortunately, the resulting yields were lower with 65% as the best result. A further drawback was the separation of PPh 3 from the product by column chromatography wherefore the two-step procedure proved to be the method of choice.
With this procedure for thianthrenes in hand, we tried to expand the scope to other heterocyclic scaffolds. Therefore, alkynes 4 bearing an electron-withdrawing group were utilised resulting in benzo [b][1,4]dithiines. 13 Slight adjustments of the reaction conditions were necessary to obtain the desired products, but in all cases much faster transformations were observed using these polarised alkynes. 14 Consequently, dimethylester 7aa and mono-methylester 7ab were reached in 75% and 57% yields, respectively (Table 3).   Michael acceptors based on ketones could be converted in yields of 72% for 7ac and 77% for 7ad. Modifications regarding the dithioloimine core were performed as well. Methyl-substituted dimethylester derivative 7ba could be achieved in 72% yield. Also, other heterocyclic systems could be introduced resulting in pyrazine 7ca and thiadiazol 7da and in 75% and 66% yield. In addition, the application of Michael acceptors based on double bonds was unsuccessful. We assume that in such a case the retro-Michael reaction in contrast to the ring closure is the preferred mode of action. 15 Encouraged by these results, we investigated whether also nitrogen might play the nucleophilic role. Changing the aromatic core to 2-thiocyanatopyrrole the endocyclic nitrogen should be prone to act as nucleophile. As result, the analogous transformation under modified reaction conditions yielded the desired benzo[d]pyrrolo[2,1-b]thiazole 16 (9) in 45% yield (Scheme 3).
Further, also Michael acceptors were shown to be suitable substrates to afford the corresponding pyrrolo[2,1-b]thiazole 17 derivatives 10ad, 10ba and 10bb in 50-63% yield ( Table 4). Because of the high reactivity and amphiphilic character of 8, it rather tends to undergo a homocoupling than a 1,4-addition. This problem was partially counteracted by applying higher loadings of Michael acceptor.
We propose the following plausible reaction mechanisms being responsible for product formation (Scheme 4). Precursor 2a is transformed into the reactive aryne. Deprotonation of benzodithioloimine favours the nucleophilic attack on the aryne leading to intermediate A (Scheme 4a). This species undergoes a concomitant nucleophilic substitution on sulphur, whereby nitrile acts as leaving group to form product 3aa. The pivotal reaction steps for alkynes substituted with electronwithdrawing groups are similar (Scheme 4b). Nevertheless, in this case the formation of the reactive triple bond is not necessary resulting in shorter reaction times in comparison with the previous transformation. The proposed reaction mechanisms are supported by side products 12 and 13 which are formed if ring-closure stays out because of protonation of intermediate A or B (Scheme 4c).
Scheme 4 Proposed mechanistic scenario: (a) for the reaction with arynes; (b) for the reaction with Michael acceptors; (c) observed side products.
The use of 2-thiocyanatopyrroles paves the way for a novel, fast and efficient entry to benzo[d]pyrrolo [2,1-b]thiazoles and pyrrolo[2,1-b]thiazoles, respectively. Further studies to expand this methodology to other heterocyclic scaffolds are ongoing. This research was supported by the German Research Foundation (DFG, Emmy Noether and Heisenberg Fellowships to D.B.W.) and by the Fonds der Chemischen Industrie (PhD Fellowship to M.P. and Dozentenstipendium to D.B.W.). L.K.B.G. thanks the Studienstiftung des deutschen Volkes for a PhD Fellowship.