Synthesis of [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines

The reactions of 2-, 3- and 4-aminopyridines with 4,5-dichloro-1,2,3-dithiazol-ium chloride (Appel salt) 4 to give N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-X-amines 1a (X = 2), 1g (X = 3) and 1k (X = 4) were optimized with respect to base, temperature and reaction time. Based on these conditions a total of thirteen [(dithiazol-ylidene)amino]azines 1a-m were prepared and fully characterized.

To improve the yields in the above reactions we then screened a variety of amine bases. Weakly aromatic amine bases like pyridine (pK b 8.8) and the more sterically demanding (less nucleophilic) lutidine (pK b 7.4) were included, as well as a range of trialkylamines with increasing steric demands, reduced nucleophilicity and increasing basicity e.g., DABCO (pK b 5.2), Et 3 N (pK b 3.4), and Hünig's base (pK b 2.6), and "weakly" nucleophilic strong amidine bases such as DBU (pK b 1.1) and DBN (pK b 0.5) [27].
The addition of base was needed to obtain greater than trace quantities of (dithiazolylidene)pyridinamines. Furthermore, increasing the reaction time (by 4, 6 and 8 h) before or after the addition of base, decreased the yields. Increasing the reaction temperature from 25 to 40 C also did not lead to an improvement of the observed yields. The best conditions required mixing Appel salt 4 with the aminopyridine for 1 h at room temperature followed by the addition of amine base (2 equiv.) and a further 2 h of stirring (Table 1).

Scheme 2. Zwitterionic resonance forms for 2-and 4-aminopyridines.
Also notable was that the reaction between 2-aminopyridine and Appel salt 4 was less sensitive to the base used, which tentatively may be attributed to two factors: (1) The pyrid-2-yl nitrogen's ability to coordinate with the dithiazole sulfur S-1 in a "non-bonding" manner [29,30] provided particularly stable (dithiazolylidene)pyridinamines; and (2) the acidity of the proton in intermediate 6 was enhanced by both the neighbouring pyridyl nitrogen and the positively charged dithiazolium ring sulfur [9,23]. Both these features could lead to a very facile base catalysed elimination of HCl (Scheme 3).

Synthesis of a [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azine Library
To investigate this further, a range of substituted aminopyridines and related azines were reacted with Appel salt 4 in the presence of the above amine bases ( Table 2). In nearly all cases the substituents (Me, Hal, CN, and NO 2 ) on the aminoazine had little effect on the product yields. The exception to this was the use of 3-aminopyridin-2-one, which only gave good yields (53%) of the dithiazolylideneamine 1h when pyridine was used as base. As before, the position of the nitrogen atom in the aromatic ring affected the product yields. In the case of 2-and 3-amino derivatives the desired [(dithiazolylidene)amino]azines were obtained in moderate to good yields. 4-Aminopyridines gave very low yields with all the bases as expected; however, the presence of an additional nitrogen atom α to the amine as in 4-aminopyrimidine-5-carbonitrile led to the formation of the dithiazolylideneamine 1m in moderate to good yields (15-61%).

General
Reactions were protected from atmospheric moisture by CaCl 2 drying tubes. Anhydrous Na 2 SO 4 was used for drying organic extracts, and all volatiles were removed under reduced pressure. All reaction mixtures and column eluents were monitored by TLC using commercial glass backed thin layer chromatography (TLC) plates (Merck Kieselgel 60 F 254 ). The plates were observed under UV light at 254 and 365 nm. The technique of dry flash chromatography was used throughout for all non-TLC scale chromatographic separations using Merck Silica Gel 60 (less than 0.063 mm). Melting points were determined using a PolyTherm-A, Wagner & Munz, Koefler-Hotstage Microscope apparatus. Solvents used for recrystallization are indicated after the melting point. UV spectra were obtained using a Perkin-Elmer Lambda-25 UV/vis spectrophotometer and inflections are identified by the abbreviation 'inf'. IR spectra were recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer with a Pike Miracle Ge ATR accessory 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 300 instrument (at 300 and 75 MHz, respectively). 13 C-DEPT NMR was used to identify quaternary and tertiary carbons, which are indicated by (s) and (d) notations, respectively. Deuterated solvents were used for homonuclear lock and the signals are referenced to the deuterated solvent peaks. Low resolution (EI) mass spectra were recorded on a Shimadzu Q2010 GC-MS with direct inlet probe.

Conclusions
The reaction conditions for the synthesis of a series of [(4-chloro-5H-1,2,3-dithiazolylidene)amino]azines were optimized with respect to base, temperature and reaction time. The optimum conditions involved mixing the aminoazine with Appel salt 4 in DCM at room temperature for 1 h, followed by the addition of amine base (2 equiv.) and then an additional 2 h of stirring at room temperature. Thirteen N-heteroazinyl dithiazolimines were successfully synthesized. With 2-pyridylamines, the choice of base was less important than with the 3-and 4-pyridylamines. In these cases the use of trialkylamines such as Et 3 N and Hünig's base often gave superior product yields.