DMSO-HCl system as an efficient oxidant of thioamides and selenoamides

(2Е,2'E)-2,2'-(1,2,4-Thiadiazole-3,5-diyl)bis(3-arylacrylonitriles) were obtained by shorttime heating of 3-aryl-2-cyanoprop-2-enethioamides with DMSO–HCl system. Under the same conditions, cyclic thioamides (2-thioxo-1,2-dihydropyridine-3-carbonitriles and quinoxaline2(1Н)-thione) reacted to form bis(hetaryl)disulfides in good yields (65-91%). When treated with DMSO–HCl, ethyl 4-(4-chlorophenyl)-5-cyano-2-phenyl-6-thioxo-1,4,5,6-tetrahydropyridine-3carboxylate afforded a mixture of products of oxidation at sulfur atom and hetero ring. The oxidation of N-aryl-4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carboxamides leads to isothiazolo[5,4-b]pyridines. 3-Aryl-2-cyanoprop-2-eneselenoamides reacted with DMSO–HCl to give (2Е,2'E)-2,2'-(1,2,4-selenadiazole-3,5-diyl)bis(3-arylacrylonitriles).


Introduction
Dimethylsulfoxide activated by various electrophilic agents have been recognized as an effective and versatile oxidant widely used in modern practice of organic synthesis [1][2][3][4][5]. One of the most common and available reagents of this type is DMSO dopped with HCl. DMSO-HX (X = Cl, Br) system have been successfully used for oxidation of acetophenones to arylglyoxals [6], halogenation of aromatic compounds [7], as well as for the oxidative dimerization of primary thioamides and thioureas to 3,5-disubstituted 1,2,4-thiadiazoles [8,9]. The mechanism of the latter reaction is discussed [9][10][11]. Noteworthy that in the presence of acetone or its homologs, thiourea derivatives react with DMSO-HCl system to afford 2-aminothiazoles and 2iminothiazolines [11]. This method represents an alternative to the classical Hantzsch thiazole synthesis and allows thiazole derivatives without using α-halocarbonyl compounds.
In continuation of our studies in the field of chemistry of cyanothioacetamide, cyanoselenoacetamide and their cyclic derivatives, we decided to study the behavior of a number of linear and cyclic thioamides 1-5 and selenoamides 6 in the reactions with DMSO-HCl and DMSO-HCl-acetone systems.
When a solution of 3-aryl-2-cyanoprop-2-enethioamides 1 in DMSO was treated with 30% HCl at 25 °C, a rapid reaction accompanied by formation of dimethyl sulfide and elemental sulfur was observed. The main products were identified as 1,2,4-thiadiazoles 7 (Scheme 1). Structure of thiadiazoles 7 was confirmed by the spectral data (LC/MS, 1 H NMR, 13 C NMR, IR) and results of microanalysis.
By analogy with thioamides, 3-aryl-2-cyanoprop-2-eneselenoamides 6 reacted with DMSO-HCl to give 1,2,4-selenadiazoles 8, which are derivatives of a relatively rare heterocyclic system. The reaction is accompanied by elimination of elemental Se and Me 2 S, and proceeds smoothly in acetone solution.
The reaction of thioamides 1 with DMSO-HCl-acetone system under similar conditions gave the same products of the oxidative dimerization, namely, thiadiazoles 7. No products of reactions involving acetone were observed or isolated, even when a large excess of acetone used. Moreover, acetone was found to be a suitable solvent for oxidation of thioamides 1 and selenoamides 6. The use of excessive amounts of DMSO or HCl provides more rapid and complete conversion of a substrate and does not affect the yields of the target products. (E)-3-(4-Hydroxy-3-methoxyphenyl)-2-cyanoprop-2-enethioamide (1a) was also subjected to oxidation in the presence of hexanone-2, cyclohexanone, ethyl acetoacetate and acetylacetone. In all cases only thiadiazole 7a (Ar = 4-HO-3-MeOC 6 H 3 ) has been isolated. The only products obtained from the oxidation of 2-thioxo-1,2-dihydropyridine-3carbonitriles 2 with DMSO-HCl and DMSO-HCl-acetone systems were bis(pyrid-2-yl)disulfides 9. The yields of disulfides 9 are good to excellent. It should be noted that oxidation of tetrahydropyridines 3 (Ar 1 = 4-ClC 6 H 4 ) leads to a mixture of disulfide 10a and 1,4-dihydro analog 10b in ~3:1 ratio. The addition of DMSO and HCl to a boiling suspension of 3phenylquinoxaline-2(1H)-thione 4 in acetone leads to the formation of the corresponding disulfide 11 in 88% yield. In contrast, the oxidation of 2-thioxonicotinamides 5 gives only isothiazolopyridines 12. In this case, the neighborhood of C=S and carbamoyl fragments favors the oxidative cyclization to form isothiazole ring.
In summary, the DMSO-HCl system can be successfully used for the oxidation of various thioamides and selenoamides. The structures of end products are strongly dependent on the structures of substrates. The proposed methods for synthesis of 1,2,4-thiadiazoles, isothiazolopyridines and bis(hetaryl)disulfides are highly effective and allow high yields, simplicity and clean-processing. It should be noted that DMSO and HCl are exceptionally available and low cost reagents. To the solution formed, 0.5 mL (4.7 mmol) of 30% HCl (d = 1.15 g/cm 3 ) was added dropwise under vigorous stirring. For a moment the reaction mixture turned red, then discoloration and turbidity (formation of colloidal sulfur) or red/black precipitate formation (elemental Se) were observed. (Caution! Dimethylsulfide evolved!). The mixture was quickly filtered through a large pore paper filter to separate sulfur/selenium. The resulting solution was stirred at reflux temperature for 1-2 minutes with a partial evaporation of acetone, then allowed to cool, diluted with 5 mL of EtOH and kept for 24-48 h at 20 °C. The precipitate was filtered off, washed with EtOH. The reaction can also be carried out in the absence of acetone in pure DMSO, following by precipitation of the end products with EtOH and/or water and recrystallization from an appropriate solvent to remove S/Se impuruties. In this case, the yields of thiadiazoles/selenadiazoles are somewhat lower, probably because of their good solubility in DMSO.
Representative example: