5,5′-Thiobis(3-methoxy-4H-1,2,6-thiadiazin-4-one)

The reaction of 3-chloro-5-methoxy-4H-1,2,6-thiadiazin-4-one (9) with Na2S·9H2O (0.5 equiv) in tetrahydrofuran (THF) at ca. 20 °C for 20 h gives 5,5′-thiobis(3-methoxy-4H-1,2,6-thiadiazin-4-one) (10) in a 44% yield as yellow needles. The compound was fully characterized.

As part of our ongoing interest with 1,2,6-thiadiazines, we investigated the synthesis of a thioamide functional group onto the 1,2,6-thiadiazine ring. Thioamide-containing azaarenes including pyridines and pyrimidines have numerous uses in medicinal chemistry. For example, pyridine 1 was a weak AChE inhibitor [16], pyridine 2 was investigated as a metaloenzyme inhibitor [17], while pyridine 3 is a reverse transcriptase inhibitor and is useful as an anti-HIV agent [18] (Figure 1).
As part of our ongoing interest with 1,2,6-thiadiazines, we investigated the synthesis of a thioamide functional group onto the 1,2,6-thiadiazine ring. Thioamide-containing azaarenes including pyridines and pyrimidines have numerous uses in medicinal chemistry. For example, pyridine 1 was a weak AChE inhibitor [16], pyridine 2 was investigated as a metaloenzyme inhibitor [17], while pyridine 3 is a reverse transcriptase inhibitor and is useful as an anti-HIV agent [18] ( Figure 1). 1,2,6-thiadiazines could act as isosters to other 6-membered hetarenes; therefore, the formation of a thioamide onto the thiadiazine could offer a new scaffold for the synthesis of biologically active 1,2,6-thiadiazines could act as isosters to other 6-membered hetarenes; therefore, the formation of a thioamide onto the thiadiazine could offer a new scaffold for the synthesis of biologically active molecules. Some related amide-containing thiadiazines have been prepared, such as thiadiazinone 5, which can exist in the tautomeric form 5 by the displacement of the C-5 chloride of dichlorothiadiazinone 4 with hydroxide [19] (Scheme 1). Moreover, an attempt to deprotect benzyloxy derivative 6 led to the benzyl group migration to the N-2 position, yielding amide 7 along with the deprotected thiadiazine 8 [20] (Scheme 1).
molecules. Some related amide-containing thiadiazines have been prepared, such as thiadiazinone 5, which can exist in the tautomeric form 5′ by the displacement of the C-5 chloride of dichlorothiadiazinone 4 with hydroxide [19] (Scheme 1). Moreover, an attempt to deprotect benzyloxy derivative 6 led to the benzyl group migration to the N-2 position, yielding amide 7 along with the deprotected thiadiazine 8′ [20] (Scheme 1). Scheme 1. Synthesis of amide-containing thiadiazines.

Results and Discussion
The above reactions showing the displacement of the C-5 chloride of dichlorothiadiazinone 4 with hydroxide [19], or other oxygen nucleophiles [15], prompted us to investigate the use of sulfide as a nucleophile that could afford the desired thiadiazine-thioamide. It is worthy of note that 3chloro-1,2,6-thiadiazines are prone to ring-opening reactions in the presence of thiophilic reagents such as phosphines, halides and nucleophilic sulfur [15].
We chose 3-chloro-5-methoxy-4H-1,2,6-thiadiazin-4-one (9) as the starting material, as the electron donating ability of the methoxy group should make the ring sulfur less prone to thiophilic attack, while the methoxy group also acted as a protecting group to avoid the formation of oligomers or polymers. Methoxy-substituted thiadiazines can readily be transformed to analogous triflates [20]. In our efforts, we failed to obtain the desired thioamide; however, from the reaction of thiadiazine 9 with Na2S in THF at ca. 20 °C, we isolated 5,5'-thiobis(3-methoxy-4H-1,2,6-thiadiazin-4-one) (10) as the only product in a 44% yield (Scheme 2, see Supplementary Materials for NMR spectra). This compound represents the first non-S-oxidized bis-1,2,6-thiadiazine sulfide. Moreover, compound 10 itself is a new chemotype with potential value in the medicinal chemistry sector. Several drugs contain heterocyclic sulfide moieties; e.g., the immunosuppressive Azathioprine. This study shows that thiadiazine sulfides can be readily synthesized, which can open up the investigation of their chemistry and properties.

Materials and Methods
The reaction mixture was monitored by thin layer chromatography (TLC) using commercial glass-backed TLC plates (Merck Kieselgel 60 F254). The plates were observed under UV light at 254 and 365 nm. Tetrahydrofuran (THF) was distilled over CaH2 before use. The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler-Hotstage Microscope apparatus (Wagner Scheme 1. Synthesis of amide-containing thiadiazines.

Results and Discussion
The above reactions showing the displacement of the C-5 chloride of dichlorothiadiazinone 4 with hydroxide [19], or other oxygen nucleophiles [15], prompted us to investigate the use of sulfide as a nucleophile that could afford the desired thiadiazine-thioamide. It is worthy of note that 3-chloro-1,2,6-thiadiazines are prone to ring-opening reactions in the presence of thiophilic reagents such as phosphines, halides and nucleophilic sulfur [15].
We chose 3-chloro-5-methoxy-4H-1,2,6-thiadiazin-4-one (9) as the starting material, as the electron donating ability of the methoxy group should make the ring sulfur less prone to thiophilic attack, while the methoxy group also acted as a protecting group to avoid the formation of oligomers or polymers. Methoxy-substituted thiadiazines can readily be transformed to analogous triflates [20]. In our efforts, we failed to obtain the desired thioamide; however, from the reaction of thiadiazine 9 with Na 2 S in THF at ca. 20 • C, we isolated 5,5 -thiobis(3-methoxy-4H-1,2,6-thiadiazin-4-one) (10) as the only product in a 44% yield (Scheme 2, see Supplementary Materials for NMR spectra). This compound represents the first non-S-oxidized bis-1,2,6-thiadiazine sulfide. Moreover, compound 10 itself is a new chemotype with potential value in the medicinal chemistry sector. Several drugs contain heterocyclic sulfide moieties; e.g., the immunosuppressive Azathioprine. molecules. Some related amide-containing thiadiazines have been prepared, such as thiadiazinone 5, which can exist in the tautomeric form 5′ by the displacement of the C-5 chloride of dichlorothiadiazinone 4 with hydroxide [19] (Scheme 1). Moreover, an attempt to deprotect benzyloxy derivative 6 led to the benzyl group migration to the N-2 position, yielding amide 7 along with the deprotected thiadiazine 8′ [20] (Scheme 1).

Results and Discussion
The above reactions showing the displacement of the C-5 chloride of dichlorothiadiazinone 4 with hydroxide [19], or other oxygen nucleophiles [15], prompted us to investigate the use of sulfide as a nucleophile that could afford the desired thiadiazine-thioamide. It is worthy of note that 3chloro-1,2,6-thiadiazines are prone to ring-opening reactions in the presence of thiophilic reagents such as phosphines, halides and nucleophilic sulfur [15].
We chose 3-chloro-5-methoxy-4H-1,2,6-thiadiazin-4-one (9) as the starting material, as the electron donating ability of the methoxy group should make the ring sulfur less prone to thiophilic attack, while the methoxy group also acted as a protecting group to avoid the formation of oligomers or polymers. Methoxy-substituted thiadiazines can readily be transformed to analogous triflates [20]. In our efforts, we failed to obtain the desired thioamide; however, from the reaction of thiadiazine 9 with Na2S in THF at ca. 20 °C, we isolated 5,5'-thiobis(3-methoxy-4H-1,2,6-thiadiazin-4-one) (10) as the only product in a 44% yield (Scheme 2, see Supplementary Materials for NMR spectra). This compound represents the first non-S-oxidized bis-1,2,6-thiadiazine sulfide. Moreover, compound 10 itself is a new chemotype with potential value in the medicinal chemistry sector. Several drugs contain heterocyclic sulfide moieties; e.g., the immunosuppressive Azathioprine. This study shows that thiadiazine sulfides can be readily synthesized, which can open up the investigation of their chemistry and properties.

Materials and Methods
The reaction mixture was monitored by thin layer chromatography (TLC) using commercial glass-backed TLC plates (Merck Kieselgel 60 F254). The plates were observed under UV light at 254 and 365 nm. Tetrahydrofuran (THF) was distilled over CaH2 before use. The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler-Hotstage Microscope apparatus (Wagner This study shows that thiadiazine sulfides can be readily synthesized, which can open up the investigation of their chemistry and properties.

Materials and Methods
The reaction mixture was monitored by thin layer chromatography (TLC) using commercial glass-backed TLC plates (Merck Kieselgel 60 F 254 ). The plates were observed under UV light at 254 and 365 nm. Tetrahydrofuran (THF) was distilled over CaH 2 before use. The melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler-Hotstage Microscope apparatus (Wagner & Munz, Munich, Germany). The solvent used for recrystallization is indicated after the melting point. The UV-vis spectrum was obtained using a Perkin-Elmer Lambda-25 UV-vis spectrophotometer (Perkin-Elmer, Waltham, MA, USA) and inflections are identified by the abbreviation "inf". The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with the Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA) and strong, medium and weak peaks are represented by s, m and w, respectively. 1 H and 13 C NMR spectra were recorded on a Bruker Avance 500 machine (at 500 and 125 MHz, respectively (Bruker, Billerica, MA, USA)). Deuterated solvents were used for homonuclear lock and the signals are referenced to the deuterated solvent peaks. Attached proton test (APT) NMR studies identified carbon multiplicities, which are indicated by (s), (d), (t) and (q) notations. The MALDI-TOF mass spectrum (+ve mode) was recorded on a Bruker Autoflex III Smartbeam instrument (Bruker). The elemental analysis was run by the London Metropolitan University Elemental Analysis Service. 3-chloro-5-methoxy-4H-1,2,6-thiadiazin-4-one (9) was prepared according to the procedure in the literature [21].