Synthesis of 6-(4-Chlorophenyl)- N -aryl-4-(trichloromethyl)-4 H - 1,3,5-oxadiazin-2-amines: A Comparative Evaluation of Dehydrosulfurization Methods of Starting 4-Chloro -N -(2,2,2 -trichloro-1-(3-arylthioureido)ethyl)benzamides

: Derivatives of 1,3,5-oxadiazine are of interest to pharmacy, medicine, and agriculture as potential biologically active substances. These compounds have found wide application in organic synthesis and supramolecular chemistry. In this paper, we discuss and compare the effectiveness of two approaches to the dehydrosulfurization of 4-chloro-N -(2,2,2-trichloro-1-(3-arylthioureido)ethyl) benzamides resulting in the formation of 6-(4-chlorophenyl)- N -aryl-4-(trichloromethyl)-4 H -1,3,5-oxadiazin-2-amines. Dicyclohexylcarbodiimide (DCC) or a mixture of iodine with triethylamine was used as a dehydrosulfurizing agent. It is shown that, in the case of using DCC, the target products are predominantly formed in high yields. However, the use of the I 2 + Et 3 N mixture made it possible to obtain several new compounds of this class, which could not be obtained under the DCC action. The structure of all new compounds was conﬁrmed by 1 H and 13 C NMR spectroscopy data.

Previously, we developed a new method for the synthesis of 4H-1,3,5-oxadiazine derivatives (3) based on the dehydrosulfurization of N-amidoalkylated thioureas (1) by the action of dicyclohexylcarbodiimide (DCC) (Scheme 1) [32][33][34][35]. It is assumed that carbodiimide 2 is formed as an intermediate, which is then closed to oxadiazine 3. This method makes it possible to obtain 1,3,5-oxadiazine derivatives in sufficiently high yields, but it is very limited in terms of the variety of possible substituents of the thioureide fragment. In some cases, products 3 could not be isolated from the reaction mixture. Therefore, we were forced to look for other dehydrosulfurizing agents, which, for example, can be used method makes it possible to obtain 1,3,5-oxadiazine derivatives in sufficiently high yields, but it is very limited in terms of the variety of possible substituents of the thioureide fragment. In some cases, products 3 could not be isolated from the reaction mixture. Therefore, we were forced to look for other dehydrosulfurizing agents, which, for example, can be used without heating. In this work, we proposed to synthesize 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines based on 4-chloro-N-(2,2,2-trichloro-1-(3-arylthioureido)ethyl)benzamides using a mixture of I2 and Et3N for dehydrosulfurization. Scheme 1. Synthesis of 4H-1,3,5-oxadiazine derivatives (3) using dicyclohexylcarbodiimide as a dehydrosulfurizing agent.

Materials and Methods
1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were measured for solutions in DMSO-d6 on a Varian VXR-400 spectrometer. Elemental analysis was performed on a LECO CHNS-900 instrument. The reaction's progress and the compounds' purity were monitored by TLC on Silufol UV-254 plates using a chloroform/acetone mixture (3:1) as an eluent.

Materials and Methods
1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were measured for solutions in DMSO-d 6 on a Varian VXR-400 spectrometer. Elemental analysis was performed on a LECO CHNS-900 instrument. The reaction's progress and the compounds' purity were monitored by TLC on Silufol UV-254 plates using a chloroform/acetone mixture (3:1) as an eluent.
Method B: A solution of 11 mmol (2.79 g) of iodine and 30 mmol (4.2 mL) of triethylamine in 10 mL of DMF was added in portions over 40 min to a solution of 10 mmol of thiourea 1 in 15 mL of DMF with stirring. The reaction mixture was left for 2-4 h at room temperature, and the precipitated sulfur was filtered. The target product was precipitated from the filtrate with an aqueous solution of sodium thiosulfate (1%, 250 mL). The precipitate formed was filtered, washed with water (2 × 50 mL), and dried. The product was purified by recrystallization from an appropriate solvent.
The 4H-1,3,5-Oxadiazine derivatives 3a-e,g-p were obtained earlier by method A, and all necessary constants and spectral data are given in [32][33][34]. Compounds 3f,q-t were obtained for the first time.

Results and Discussion
Amidoalkylated thioureas 1a-t were obtained by the addition of arylamines 4a-t to 4-chloro-N-(2,2,2-trichloro-1-isothiocyanatoethyl)benzamide (5) according to the general procedure described in [32][33][34] (Scheme 2). Thioureas 1f,q-t were obtained for the first time; other representatives of this series of compounds were known earlier. Due to the presence of several reaction centers, compounds 1a-t are of interest for the synthesis of heterocycles by the reaction of intramolecular cyclization. In addition, these compounds are structural analogs of Salubrinal [36][37][38][39][40][41] and are of interest as potential inhibitors of GADD34:PP1.

Scheme 2. Synthesis of 4-chloro-N-(2,2,2 -trichloro-1-(3-arylthioureido)ethyl)benzamides (1a-t).
Dehydrosulfurization of thioureas (1) with dicyclohexylcarbodiimide, as shown earlier [32][33][34][35], leads to the formation of 4H-1,3,5-oxadiazine derivatives 3 (Scheme 3). Using this method (Method A), we obtained several representatives of this class of Dehydrosulfurization of thioureas (1) with dicyclohexylcarbodiimide, as shown earlier [32][33][34][35], leads to the formation of 4H-1,3,5-oxadiazine derivatives 3 (Scheme 3). Using this method (Method A), we obtained several representatives of this class of compounds in fairly high yields. However, in most cases, due to the resinification of the reaction mixture, products 3 could not be isolated. Therefore, we empirically searched for other possible dehydrosulfurizing agents. We chose to use a mixture of I 2 and Et 3 N in DMF (Method B). The use of this method made it possible to exclude the heating of the reaction mixture and, as a result, to avoid its gumming. compounds in fairly high yields. However, in most cases, due to the resinification of the reaction mixture, products 3 could not be isolated. Therefore, we empirically searched for other possible dehydrosulfurizing agents. We chose to use a mixture of I2 and Et3N in DMF (Method B). The use of this method made it possible to exclude the heating of the reaction mixture and, as a result, to avoid its gumming. The use of DCC as a dehydrosulfurizing agent mainly allowed the obtaining of the target products with high yields (Figure 1). However, the use of a mixture of I2 and Et3N made it possible to obtain compounds 3f, 3r, and 3s, which could not be obtained under the action of DCC. The use of DCC as a dehydrosulfurizing agent mainly allowed the obtaining of the target products with high yields (Figure 1). However, the use of a mixture of I 2 and Et 3 N made it possible to obtain compounds 3f, 3r, and 3s, which could not be obtained under the action of DCC. The structure of all compounds was confirmed by 1 H and 13 C NMR spectroscopy data (see supporting information and [32][33][34]). The starting thioureas 1 in the 1 H NMR spectra were characterized by the presence of three NH protons, one of which appeared as a singlet (11.1-10.3 ppm) and the other two as a doublet or a broadened singlet at 9.5-8.4 ppm. Oxadiazines 3 were characterized by the presence of only one NH proton signal, which appeared at 10.5-8.7 ppm. The involvement of the amide and thioureide fragments in the cyclization was indicated by the fact that in the starting thioureas 1 the CH signal of the proton located near the trichloromethyl group manifested itself as a doublet of doublets at 7.6-7.1 ppm, while in oxadiazines 3 it appeared as a singlet at 5.80-5.50 ppm. In the 13 C NMR spectra of thioureas 1, the most characteristic signals were C=S and C=O carbons at 183-180 and 165-164 ppm, respectively. In the 13 C NMR spectra of products 3 there were no signals of C=S and C=O carbons, but signals of two C=N carbons were observed at 155-144 ppm.

Conclusions
In this work, we have proposed a new method for the dehydrosulfurization of 4-chloro-N-(2,2,2-trichloro-1-(3-arylthioureido)ethyl)benzamides (1), leading to the formation of 6-(4-chlorophenyl)-N-aryl-4-(trichloromethyl)-4H-1,3,5-oxadiazin-2-amines (3). As a dehydrosulfurizing agent, we have proposed using a mixture of iodine with triethylamine. The efficiency of using DCC and I2 + Et3N for the dehydrosulfurization of thioureas 1 has been compared. It has been shown that the target products are predominantly formed in high yields when using DCC. However, the use of a mixture of I2 and Et3N makes it possible to obtain several new compounds of this class, which cannot be obtained under the action of DCC.