New Cycloadditon Reaction of 2-Chloroprop-2-enethioamides with Dialkyl Acetylenedicarboxylates: Synthesis of Dialkyl 2-[4,5-bis(alkoxycarbonyl)-2-(aryl{alkyl}imino)-3(2H)-thienylidene]-1,3-dithiole-4,5-dicarboxylates

The 1,3-dipolar cycloaddition of 1,2-dithiole-3-thiones with alkynes to form 1,3-dithioles is one of the most studied reactions in this class of polysulfur-containing heterocycles. Nucleophilic substitution of chlorine atoms in dimethyl 2-(1,2-dichloro-2-thioxoethylidene)-1,3-dithiole-4,5-dicarboxylate, which was obtained by addition one molecules of DMAD to 4,5-dichloro-3H-1,2-dithiole-3-thione, led to a series of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides. Cycloaddition reaction of 2-chloro-2-(1,3-dithiol-2-ylidene)ethanethioamides with activated alkynes led to the unexpected formation of 2-(thiophen-3(2H)-ylidene)-1,3-dithioles via new intermediate, 1-(1,3-dithiol-2-ylidene)-N-phenylethan-1-yliumimidothioate. Structure of dimethyl 2-(4,5-bis(methoxycarbonyl)-2-(phenylimino)thiophen-3(2H)-ylidene)-1,3-dithiole-4,5-dicarboxylate was finally proven by single crystal X-ray diffraction study. Optimized reaction conditions and a mechanistic rationale for the 1,3-dipolar cycloaddition of novel intermediate are presented.


Results and Discussion
The nucleophilic substitution of dichlorothioxoethylidenedithiole 5a has been poorly studied. Known examples are reactions with benzylamine, m-toluidine, morpholine, phenol and thiophenol in acetone at room temperature with the formation of the corresponding thioamides and thiono and dithio esters 8, usually in high yields [15]. We have studied in detail the reactivity of nitrogen nucleophiles with compound 5a. Treatment of this compound with a twofold excess of aniline in MeCN gave thioamide 9a in good yield ( Table  1, Entry 1). The use of DMF instead of acetonitrile as a solvent shortened the reaction time Herein, we describe the synthesis of thioacyl amides 9 and its cycloaddition reaction with activated alkynes to unexpectedly form of thiophen-3(2H)-ylidenes 10 via new intermediate 14.

Results and Discussion
The nucleophilic substitution of dichlorothioxoethylidenedithiole 5a has been poorly studied. Known examples are reactions with benzylamine, m-toluidine, morpholine, phenol and thiophenol in acetone at room temperature with the formation of the corresponding thioamides and thiono and dithio esters 8, usually in high yields [15]. We have studied in detail the reactivity of nitrogen nucleophiles with compound 5a. Treatment of this compound with a twofold excess of aniline in MeCN gave thioamide 9a in good yield ( Table 1, Entry 1). The use of DMF instead of acetonitrile as a solvent shortened the reaction time and slightly increased the yield of final product 9a (Entry 2). The most logical and economical in terms of amine consumption seemed to be the use of one mole of a tertiary amine, i.e., trimethylamine, to bind the hydrogen chloride molecule, which is released upon reaction with the amine. It turned out that the replacement of one mole of aniline to Et 3 N or Cs 2 CO 3 led to almost the same yield of product 9a (Entries 3 and 4). Similar patterns were noted when these methods were extended to other aromatic and aliphatic amines; moderate to high yields of thioamides 9 were achieved (Entries 5, 8 and 20). For p-nitroaniline, similar conditions also turned out to be optimal, but in this case it was necessary to heat the reaction mixture to 80 • C (Entry 15). We have shown that the often more accessible and stable hydrochlorides or hydrobromides of aromatic and aliphatic amines can be successfully introduced into this reaction (Entries 7, 18 and 22). amines; moderate to high yields of thioamides 9 were achieved (Entries 5, 8 a p-nitroaniline, similar conditions also turned out to be optimal, but in this case essary to heat the reaction mixture to 80 °C (Entry 15). We have shown that the accessible and stable hydrochlorides or hydrobromides of aromatic and aliph can be successfully introduced into this reaction (Entries 7, 18 and 22).  The reaction of thioamides 9 with dimethyl acetylenedicarboxylate (DMAD) was thoroughly studied ( Table 2). Treatment of anilino derivative 9a with DMAD at elevated temperature afforded, in various solvents (o-xylene, MeCN or DMF), novel compound 10a as a yellow solid C 21 H 17 NO 8 S 3 (Entries 1, 3 and 5). There was no reaction in any solvent at room temperature (Entries 2,4). The reaction in xylene requires many hours of heating (55 h) until the starting compound 9a disappears from the reaction mixture (TLC CH 2 Cl 2 /petroleum ether-10/1). The use of acetonitrile as a solvent requires not only an elevated temperature, but also the presence of a base, triethylamine (Entry 3). Heating of the starting compounds in DMF turned out to be the most convenient; the yield of the final compound was the highest 78% (Entry 5). Table 2. Reaction of thioamides 9 with DMAD. temperature afforded, in various solvents (o-xylene, MeCN or DMF), novel compound 10a as a yellow solid C21H17NO8S3 (Entries 1, 3 and 5). There was no reaction in any solvent at room temperature (Entries 2,4). The reaction in xylene requires many hours of heating (55 h) until the starting compound 9a disappears from the reaction mixture (TLC CH2Cl2/petroleum ether-10/1). The use of acetonitrile as a solvent requires not only an elevated temperature, but also the presence of a base, triethylamine (Entry 3). Heating of the starting compounds in DMF turned out to be the most convenient; the yield of the final compound was the highest 78% (Entry 5). According to the mass spectrum, elemental analysis, and 1 H and 13 C NMR data (Supplementary Materials), compound 10a is formally a product of DMAD addition and HCl elimination. Several isomeric structures can be proposed for this product; analysis of the obtained data did not allow us to confidentially choose the structure for this compound. The structure 10a was finally confirmed by single crystal X-ray diffraction study as dimethyl 2-(4,5-bis(methoxycarbonyl)-2-(phenylimino)thiophen-3(2H)-ylidene)-1,3-dithiole-4,5-dicarboxylate ( Figure 1). According to the mass spectrum, elemental analysis, and 1 H and 13 C NMR data (Supplementary Materials), compound 10a is formally a product of DMAD addition and HCl elimination. Several isomeric structures can be proposed for this product; analysis of the obtained data did not allow us to confidentially choose the structure for this compound. The structure 10a was finally confirmed by single crystal X-ray diffraction study as dimethyl 2-(4,5-bis(methoxycarbonyl)-2-(phenylimino)thiophen-3(2H)-ylidene)-1,3-dithiole-4,5-dicarboxylate ( Figure 1). the starting compounds in DMF turned out to be the most convenient; the yield of the final compound was the highest 78% (Entry 5). According to the mass spectrum, elemental analysis, and 1 H and 13 C NMR data (Supplementary Materials), compound 10a is formally a product of DMAD addition and HCl elimination. Several isomeric structures can be proposed for this product; analysis of the obtained data did not allow us to confidentially choose the structure for this compound. The structure 10a was finally confirmed by single crystal X-ray diffraction study as dimethyl 2-(4,5-bis(methoxycarbonyl)-2-(phenylimino)thiophen-3(2H)-ylidene)-1,3-dithiole-4,5-dicarboxylate ( Figure 1).  The reaction of thioamides 9 with DMAD was extended to give thiophen-3(2H)ylidenes 10 in moderate yields (Table 2, entries 6-10). Curiously, thioamide 9g, containing dimethylthiomide group and not containing NH group, did not react with DMF even in harsh conditions (100 • C, 10 h) gradually decomposing into products, from which it was not possible to isolate individual compounds. When a mixture of thioamide 9g and DMAD was irradiated in a ratio of 1:2 in a solution of chlorobenzene with an SVD-120 UV lamp (power 120 W) for 70 min at a temperature of 25-37 • C, no new products were detected (TLC); the starting compound 9g was isolated in almost quantitative yield.
The reaction of thioamides 9 with DMAD was extended to give thiophen-3(2H)-ylidenes 10 in moderate yields (Table 2, entries 6-10). Curiously, thioamide 9g, containing dimethylthiomide group and not containing NH group, did not react with DMF even in harsh conditions (100 °C, 10 h) gradually decomposing into products, from which it was not possible to isolate individual compounds. When a mixture of thioamide 9g and DMAD was irradiated in a ratio of 1:2 in a solution of chlorobenzene with an SVD-120 UV lamp (power 120 W) for 70 min at a temperature of 25-37 °C, no new products were detected (TLC); the starting compound 9g was isolated in almost quantitative yield.

Scheme 4. Synthesis of unsymmetrical thiophen-3(2H)-ylidenes 11a,b.
The synthesis of thiophen-3(2H)-ylidenes 10 can be carried out in one pot from readily available 4,5-dichloro-3H-1,2-dithiole-3-thione 4, which is a precursor for the preparation of thioxoethylidenedithiole 5a [13]. DMAD (1 equiv.) was successively added to a solution of dithiolethione 4 and the reaction mixture was stirred for 8 h at room temperature, then amine (2 equiv.) with stirring for 2 h at room temperature, and finally DMAD with heating at 100 °C for 3 h (Scheme 5). Compounds 10 were isolated in moderate yields. In the case of 4-nitroaniline (d), the time of the second step was increased to 10 h, and in case e, methylamine hydrochloride was used and the addition of Et3N (1 eqv) was necessary.

Scheme 4. Synthesis of unsymmetrical thiophen-3(2H)-ylidenes 11a,b.
The synthesis of thiophen-3(2H)-ylidenes 10 can be carried out in one pot from readily available 4,5-dichloro-3H-1,2-dithiole-3-thione 4, which is a precursor for the preparation of thioxoethylidenedithiole 5a [13]. DMAD (1 equiv.) was successively added to a solution of dithiolethione 4 and the reaction mixture was stirred for 8 h at room temperature, then amine (2 equiv.) with stirring for 2 h at room temperature, and finally DMAD with heating at 100 • C for 3 h (Scheme 5). Compounds 10 were isolated in moderate yields. In the case of 4-nitroaniline (d), the time of the second step was increased to 10 h, and in case e, methylamine hydrochloride was used and the addition of Et 3 N (1 eqv) was necessary. denes 10 in moderate yields (Table 2, entries 6-10). Curiously, thioamide 9g, containing dimethylthiomide group and not containing NH group, did not react with DMF even in harsh conditions (100 °C, 10 h) gradually decomposing into products, from which it was not possible to isolate individual compounds. When a mixture of thioamide 9g and DMAD was irradiated in a ratio of 1:2 in a solution of chlorobenzene with an SVD-120 UV lamp (power 120 W) for 70 min at a temperature of 25-37 °C, no new products were detected (TLC); the starting compound 9g was isolated in almost quantitative yield.

Scheme 4. Synthesis of unsymmetrical thiophen-3(2H)-ylidenes 11a,b.
The synthesis of thiophen-3(2H)-ylidenes 10 can be carried out in one pot from readily available 4,5-dichloro-3H-1,2-dithiole-3-thione 4, which is a precursor for the preparation of thioxoethylidenedithiole 5a [13]. DMAD (1 equiv.) was successively added to a solution of dithiolethione 4 and the reaction mixture was stirred for 8 h at room temperature, then amine (2 equiv.) with stirring for 2 h at room temperature, and finally DMAD with heating at 100 °C for 3 h (Scheme 5). Compounds 10 were isolated in moderate yields. In the case of 4-nitroaniline (d), the time of the second step was increased to 10 h, and in case e, methylamine hydrochloride was used and the addition of Et3N (1 eqv) was necessary. Thus, 1,3-dipolar cycloaddition of thioamides 9 with DMAD led to the formation of dihydrothiophene ring in 10 with HCl extrusion. One of the possible pathways for this unusual transformation is suggested in Scheme 6. In the reaction of thioamide 9a with an alkyne molecule, the presence of non-reactive thioamide group can suppress the Diels-Alder cycloaddition to adduct 13 similarly to indole derivatives [16] in favor of Molecules 2022, 27, 6887 6 of 12 extrusion of HCl under the action of a base (Me 2 NH from DMF or Et 3 N) to form active betaine 14. This extrusion became impossible for disubstituted thioamides (i.e., 9g) and the slow decomposition of this compound was observed. Intermediate 14 readily reacted as 1,3-dipole with DMAD to form dihydrothiophene 10.
Thus, 1,3-dipolar cycloaddition of thioamides 9 with DMAD led to the formation of dihydrothiophene ring in 10 with HCl extrusion. One of the possible pathways for this unusual transformation is suggested in Scheme 6. In the reaction of thioamide 9a with an alkyne molecule, the presence of non-reactive thioamide group can suppress the Diels-Alder cycloaddition to adduct 13 similarly to indole derivatives [16] in favor of extrusion of HCl under the action of a base (Me2NH from DMF or Et3N) to form active betaine 14. This extrusion became impossible for disubstituted thioamides (i.e., 9g) and the slow decomposition of this compound was observed. Intermediate 14 readily reacted as 1,3-dipole with DMAD to form dihydrothiophene 10.

Scheme 6.
A plausible mechanism for the formation of dihydrothiophene 10a from thioamide 9a.

Analytical Instruments
The melting points were determined on a Kofler hot-stage apparatus and were uncorrected. 1 H and 13 C NMR spectra were taken with a Bruker AM-300 machine (Bruker Ltd., Moscow, Russia) with TMS as the standard. J values are given in Hz. MS spectra (EI, 70 eV) were obtained with a Finnigan MAT INCOS 50 instrument (Thermo Finnigan LLC, San Jose, CA, USA). High-resolution MS spectra were measured on a Bruker micrO-TOF II instrument using electrospray ionization (ESI). IR spectra were measured with a Bruker "Alpha-T" instrument (Bruker, Billerica, MA, USA) in KBr pellets.

X-ray Analysis
Scheme 6. A plausible mechanism for the formation of dihydrothiophene 10a from thioamide 9a.

Analytical Instruments
The melting points were determined on a Kofler hot-stage apparatus and were uncorrected. 1 H and 13 C NMR spectra were taken with a Bruker AM-300 machine (Bruker Ltd., Moscow, Russia) with TMS as the standard. J values are given in Hz. MS spectra (EI, 70 eV) were obtained with a Finnigan MAT INCOS 50 instrument (Thermo Finnigan LLC, San Jose, CA, USA). High-resolution MS spectra were measured on a Bruker micrOTOF II instrument using electrospray ionization (ESI). IR spectra were measured with a Bruker "Alpha-T" instrument (Bruker, Billerica, MA, USA) in KBr pellets.

X-ray Analysis
X-ray diffraction data were collected at 100K on a four-circle Rigaku Synergy S diffractometer equipped with a HyPix600HE area-detector (kappa geometry, shutterless ω-scan technique), using graphite monochromatized Cu K α -radiation. The intensity data were integrated and corrected for absorption and decay by the CrysAlisPro program [19]. The structure was solved by direct methods using SHELXT and refined on F 2 using SHELXL-2018 [20] in the OLEX2 program [21]. All non-hydrogen atoms were refined with individual anisotropic displacement parameters. All hydrogen atoms were placed in ideal calculated positions and refined as riding atoms with relative isotropic displacement parameters. The Cambridge Crystallographic Data Centre contains the supplementary crystallographic data for this paper No. CCDC 2205782 (10a). 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 CB2 1EZ, UK; Fax: +44-1223-336033; E-mail: deposit@ccdc.cam.ac.uk). Crystal data and structure refinement for this compound are given in Table 3.

General Procedure for the Synthesis of Thioamides 9a-g
Amine a,b,c,f (2 mmol) or amine d,e,g (1 mmol) together with Et 3 N (0.277 mL, 2 mmol) were added to a solution of thiochloride 5a (345 mg, 1 mmol) in DMF (10 mL), and the reaction mixture was stirred at the temperature and for the time indicated in Table 1, then poured into water (60 mL) and stirred for 30 min, extracted with ethyl acetate (2 × 30 mL). Combined organic extracts were washed with dilute HCl (10%, 30 mL), brine (2 × 30 mL), dried with MgSO 4 . The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (Silica gel Merck 60, eluent CH 2 Cl 2 /petroleum ether-10/1).