Regioselective synthesis of heterocyclic N-sulfonyl amidines from heteroaromatic thioamides and sulfonyl azides

N-Sulfonyl amidines bearing 1,2,3-triazole, isoxazole, thiazole and pyridine substituents were successfully prepared for the first time by reactions of primary, secondary and tertiary heterocyclic thioamides with alkyl- and arylsulfonyl azides. For each type of thioamides a reliable procedure to prepare N-sulfonyl amidines in good yields was found. Reactions of 1-aryl-1,2,3-triazole-4-carbothioamides with azides were shown to be accompanied with a Dimroth rearrangement to form 1-unsubstituted 5-arylamino-1,2,3-triazole-4-N-sulfonylcarbimidamides. 2,5-Dithiocarbamoylpyridine reacts with sulfonyl azides to form a pyridine bearing two sulfonyl amidine groups.

A few representatives of N-sulfonyl amidines of heteroaromatic acids have been prepared and applied [22,32,[38][39][40]. However, no efficient and general method to prepare a series of hetero-cyclic N-sulfonyl amidines has been elaborated so far. A new approach to N-sulfonyl amidines has been published recently, based on the reaction of thioamides with sulfonyl azides [33,41,42] (Figure 2). This method was used successfully for the synthesis of N-sulfonyl amidines of aliphatic acids and benzoic acid, including bio-logically active compounds. On the other hand, reactions of thioamides with electrophilic reagents have often been used for the synthesis of various types of sulfur containing heterocyclic compounds [43][44][45][46][47]. This gives some promise to the development of a general and efficient method for the synthesis of N-sulfonyl amidines of heteroaromatic acids based on the reaction of heterocyclic thioamides with higly electrophilic sulfonyl azides.
With the purpose of the synthesis of heterocyclic N-sulfonyl amidines bearing various heteroatoms in the ring, namely nitrogen, sulfur and oxygen atoms, we have studied reactions of thioamides of 1,2,3-triazole-, isoxazole-, thiazolecarboxylic acids and 2,5-dithiocarbamoylpyridine with sulfonyl azides. Due to the high dipole moment, the presence of electronegative heteroatoms bearing electron lone pairs, one could propose alternative reactions which might make it difficult to find a general regioselective procedure for the synthesis of the target molecules in good yields. To the best of our knowledge, there are no examples for the synthesis of N-sulfonyl amidines of heteroaromatic acids through this reaction so far.
From these data we can conclude that the yield of the final product is optimal for the reaction under solvent-free conditions. 1-Butyl-1,2,3-triazole 1с reacts faster than 1,2,3-triazole-4-carbothioamide 1f while using a lower amount of a sulfonyl azide (Table 1, entry 11 and Table 2, entry 14). Thus solventfree conditions, a temperature of 88 °C and a thioamide/azide ratio of 1:2.5 are optimal to prepare N-sulfonyl amidine 1c (entry 11, Table 1).
The reaction can be applied without problems to various alkyl substituents in position 1 of the 1,2,3-triazole ring from methyl to decyl and benzyl, goes well with alkylsulfonyl azides and arylsulfonyl azides that were 4-substituted with both electronwithdrawing and electron-donating substituents.
We have found that thioamide 1e did react with benzenesulfonyl azide (2c) neither in water, ethanol nor in the absence of a solvent, conditions that were successfully used in the synthesis  of 1-alkyl-1,2,3-triazole-4-N-sulfonylimidamides 3a-s (Scheme 2). On the other hand, we have found the formation of a new product 3t in low yield together with the starting compound 1e and the product of its rearrangement to 5-(4-nitrophenyl)aminotriazole 1j [54], when the reaction was carried out in n-butanol at 105 °C (Table 2). Therefore, we can conclude that compound 3t was the product of a tandem reaction involving first the rearrangement of thioamide 1e to 1j followed by iminosulfonylation of the latter to form amidine 3t (Table 2).
To obtain higher yields of sulfonyl amidines we decided to prepare 5-arylamino-1,2,3-triazole-4-carbothioamide 1j by rearrangement of triazole 1e [54] and carried out an optimization with variations of the solvent, temperature and various additives (Table 2). We have shown that optimal conditions include the use of n-propanol, a temperature of 97 °C and a ratio of thioamide 1j and azide 2c of 1:7 which allowed to prepare the desired compound 3t in 78% (Table 2).
With the optimal conditions in hand we prepared a series of N-sulfonyl amidines 3t-aa in good yields (Scheme 3). Thus, a library of N-sulfonyl amidines bearing differently substituted 1,2,3-triazoles was successfully prepared. Among them are compounds bearing an NH-unsubstituted 1,2,3-triazole ring To show the practical convenience of the developed method we tried to synthesize these compounds in a one-pot procedure starting from readily available 1-aryl-1,2,3-triazoles 1f,g,t and sulfonyl azides 2c,f (Table 3). Thioamides 1f,g,t were converted to 5-arylamino-1,2,3-triazoles 1i-k by heating at reflux in n-propanol in the presence of DBU and these rearranged thioamides were then treated with sulfonyl azide 2c,f and kept at the same temperature for 17-31 h. After flash column chromatography, pure N-sulfonyl amidines 3t,u,x were isolated in 41-65 % yield. The data of Table 3 demonstrates that the yields of sulfonyl amidines 3t,u,x are higher when we used the onepot protocol in comparison with the two-step method. Furthermore, the one-pot procedure is obviously more simple and less time consuming.

2-Aminothiazole-4-N-sulfonyl amidines
In spite of the presence of a nucleophilic amino group capable to react with sulfonyl azide to form an azide group, the reaction of azides 2 occurred selectively to the thioamide group of compound 1m.
The reaction takes place also in the absence of a solvent, albeit in lower yields. We have found that secondary thioamide 1o does not react with sulfonyl azides 2a,c either in n-propanol or in the absence of a solvent. On the other hand, we have found that the reaction can occur in n-butanol at 118 °C to form compounds 3ah-ai in low yields (38-45%) accompanied with the formation of tar-like products.

2,5-Bis(N-sulfonylamidino)pyridines
Bis(thioamide) 1p containing a pyridine ring was found to react with sulfonyl azides 2a,c-f either in boiling propanol or in the absence of a solvent to form compounds 3aj-an bearing two N-sulfonyl amidine fragments connected to a pyridine linker. The solvent-free protocol includes the use of a lower amount of azide 2d,c,f (2.5 equiv) in comparison with the reaction in n-propanol (4 equiv of azide) to afford the desired products in the same yield and therefore was selected as the method of choice for the synthesis of 3aj-an (Scheme 6). The synthesis of complexes of bis(sulfonyl amidines) 3aj-an with metals is in progress. 1 H and 13 C NMR spectra including 2D HMBC and HSQC experiments of compounds 3a-an, as well as high-resolution mass spectra are consistent with the proposed structures. Carbon signals of the amidine groups of compounds 3 appear at 154.1-159.7 ppm which is close to 156 ppm which is the value found for N-sulfonyl amidines of 1,2,3-thiadiazole-4-carboxylic acid prepared by another method [22] and was clearly different from the thioamide carbon signal at 185-187 ppm in the 13 C NMR spectra of starting materials 1. A final proof of the structures of the prepared compounds comes from the X-ray data for 3e,t,ag (Schemes 2, 3, and 5). Moreover, the X-ray data reveal the existence of N-sulfonyl amidines 3e,t in the E-isomeric form and N-sulfonyl amidine 3ag in Z-isomeric form. The existence of the latter in the Z-isomeric form can be explained by steric hindrance between the phenyl and the arylsulfonyl groups.
Because of the observed evolution of nitrogen and sulfur in every reaction of heterocyclic thioamides and sulfonyl azides it is logic to propose the formation of a thiatriazole ring via [3 + 2] cycloaddition of the azide group and the C=S moiety of the thioamide group (Scheme 7).
The formation of nitrene-like products was excluded because of the high selectivity of the process, where only the thioamide group takes part, even with heterocyclic rings that contain other nucleophilic centers, and in one case, an amino group. Thiatriazoles are known to be unstable compounds that readily evolve nitrogen and sulfur upon heating [56].

Conclusion
We have shown that the reaction of sulfonyl azides with thioamides can serve as the basis for a general and efficient method for the regioselective synthesis of N-sulfonyl amidines of azolyl and pyridine carboxylic acids. The most promising aspect for organic synthesis and green chemistry is a solventfree process which was successfully applied to prepare sulfonyl amidines containing pyridine and isoxazolyl rings and 1-alkyl-1,2,3-triazole-4-N-sulfonylamidino-1,2,3-triazoles. The 1-alkyltriazole thioamides are the most active in the solvent-free method due to their low melting points and good solubility in alkyl-and arylsulfonyl azides. Conversely, thioamides containing 5-arylamino-1,2,3-triazole and 2-aminothiazole rings are not soluble in sulfonyl azides and could be transformed to the corresponding N-sulfonyl amidines by reactions in 1-propanol via two-or one-pot procedures. Pyridine-2,6-dithioamide was shown to react with mesyl and arylsulfonyl azides to form pyridine derivatives bearing two N-sulfonyl amidine moieties in excellent yield. Depending on the structure of the heterocycle the N-sulfonyl amidines exist in either E-or Z-isomeric forms. Experimental X-ray diffraction study X-ray analyses were accomplished on an Xcalibur 3 diffractometer using the standard procedure (graphite-monochromated Mo Kα irradiation, ω-scanning with step 1o, T = 295(2) K (see Supporting Information File 3). Using Olex2 [57], the structures were solved with the Superflip [58] structure solution program using charge flipping and refined with the ShelXL [59] refinement package using least squares minimization. Deposition numbers for compounds 3e (2020829), 3t (2020831) and 3ag (2020830), contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http:// www.ccdc.cam.ac.uk/data_request/cif.