Next Article in Journal
Effects of Polysaccharide Elicitors from Endophytic Fusarium oxysporium Dzf17 on Growth and Diosgenin Production in Cell Suspension Culture of Dioscorea zingiberensis
Next Article in Special Issue
One-Pot Synthesis of Novel 2,3-Dihydro-1H-indazoles
Previous Article in Journal
Optimization of an Efficient Semi-Solid Culture Protocol for Sterilization and Plant Regeneration of Centella asiatica (L.) as a Medicinal Herb
Previous Article in Special Issue
Synthesis, Acidity Constants and Tautomeric Structure of the Diazonium Coupling Products of 2-(Benzylsulfanyl)-7H-purin-6-one in Its Ground and Excited States
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 16
Issue 11
10.3390/molecules16118992
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Panayiotis A. Koutentis
*,
Maria Koyioni
and
Sophia S. Michaelidou
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
*
Author to whom correspondence should be addressed.
Molecules 2011, 16(11), 8992-9002; https://doi.org/10.3390/molecules16118992
Submission received: 26 September 2011 / Revised: 21 October 2011 / Accepted: 21 October 2011 / Published: 25 October 2011
(This article belongs to the Special Issue Heterocycles)
Browse Figures
Versions Notes

Abstract

:
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.

Graphical Abstract

1. Introduction

Select N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anilines (N-aryl-1,2,3-dithiazol-5H-imines) show interesting antitumor [1], antibacterial [2,3,4], antifungal [5,6,7], and herbicidal [8] activity. The biological activity could be due to the 1,2,3-dithiazole ring, that acts as an inhibitor of several enzymes that are structurally related to serine proteases [9]. Furthermore, N-aryldithiazolimines are useful precursors to other heterocycles. For example the thermolysis of N-aryldithiazolimines can afford benzothiazoles [10,11], benzimidazoles [12], thiazolopyridines [13] and benzoxazines [14]. Moreover, N-aryldithiazolimines can also be transformed into useful acyclic functionalities such as cyanothio-formanilides [15,16,17], N-arylcyanoformimidoyl chlorides [10,18] and N-arylisothiocyanates [19,20].
Despite their synthetic utility the library of dithiazolimines prepared from Appel salt 4 is comprised mainly of analogues where the dithiazolimine moiety is bound to a benzene ring. Some examples also exist where the dithiazole moiety is bound to 5-membered heteroles [21,22,23], but to the best of our knowledge the only reported examples, where the dithiazolimine moiety is bound directly to a 6-membered azine, are N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-2-amine (1a) [24], N3-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-N2-phenylpyridine-2,3-diamine (2) [25] and N2,N3-bis(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridine-2,3-diamine (3) [25] (Figure 1).
Molecules 16 08992 g001 550
Figure 1. Structures of known N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridinamines.
Figure 1. Structures of known N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridinamines.
Molecules 16 08992 g001
This may be due to the fact that electron poor aminoazines, such as aminopyridines, have less nucleophilic character than primary anilines. This can lead to low yields of the desired [(4-chloro-5H-1,2,3-dithiazolylidene)amino]azines and/or complex reaction mixtures due to side reactions [26]. As such, it was decided to study the synthesis of the less explored [(4-chloro-5H-1,2,3-dithiazol-ylidene)amino]azines. Herein we wish to report our results.

2. Results and Discussion

2.1. Studies on N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)pyridinamines

Our investigation began with the reaction of the simplest aminoazines, namely aminopyridines, with Appel salt 4 to afford N-(4-chloro-5H-1,2,3-dithiazolylidene)pyridin-X-amines (where X = 2, 3 and 4). By focusing of the 2-, 3- and 4-aminopyridines we hoped to see how the position of the pyridyl ring nitrogen affected the reactivity of the aminoazine with Appel salt 4. These reactions were optimized with respect to base, temperature, and reaction time (Scheme 1).
Molecules 16 08992 g002 550
Scheme 1. Preparation of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridinamines 1a, 1g and 1k.
Scheme 1. Preparation of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridinamines 1a, 1g and 1k.
Molecules 16 08992 g002
Initially the synthesis of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridinamines 1a, 1g and 1k was based on a well established literature procedure for the preparation of (dithiazolylideneamino)arenes [24], using pyridine (2 equiv.) as base, at ca. 20 °C in DCM (Scheme 1). It became clear even at this stage that the product yields were affected by the position of the pyridyl nitrogen: The reaction between 2-, 3- and 4-aminopyridines and Appel salt 4 gave the corresponding N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-X-amines 1a (X = 2), 1g (X = 3) and 1k (X = 4) in 69, 24 and 1% yields, respectively.
To improve the yields in the above reactions we then screened a variety of amine bases. Weakly aromatic amine bases like pyridine (pKb 8.8) and the more sterically demanding (less nucleophilic) lutidine (pKb 7.4) were included, as well as a range of trialkylamines with increasing steric demands, reduced nucleophilicity and increasing basicity e.g., DABCO (pKb 5.2), Et3N (pKb 3.4), and Hünig’s base (pKb 2.6), and “weakly” nucleophilic strong amidine bases such as DBU (pKb 1.1) and DBN (pKb 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).
Table
Table 1. Reaction of Appel salt 4 (2.18 mmol) with aminopyridines (2.18 mmol) in DCM (4 mL) at ca. 20 °C for 1 h and followed by base (4.36 mmol) for another 2 h.
Table 1. Reaction of Appel salt 4 (2.18 mmol) with aminopyridines (2.18 mmol) in DCM (4 mL) at ca. 20 °C for 1 h and followed by base (4.36 mmol) for another 2 h.
AminopyridineBase (pKb)Yields of 1a, 1g or 1k (%)
Pyridin-2-amine Pyridine (8.8)1a (69)
2,6-Lutidine (7.4)1a (72)
Dabco (5.2)1a (55)
Et3N (3.4)1a (69)
i-Pr2NEt (2.6)1a (73)
DBU (1.1)1a (58)
DBN (0.5)1a (47)
Pyridin-3-amine Pyridine (8.8)1g (24)
2,6-Lutidine (7.4)1g (45)
Dabco (5.2)1g (8)
Et3N (3.4)1g (43)
i-Pr2NEt (2.6)1g (57)
DBU (1.1)1g (16)
DBN (0.5)1g (13)
Pyridin-4-aminePyridine (8.8)1k (traces)
2,6-Lutidine (7.4)1k (traces)
Dabco (5.2)1k (3)
Et3N (3.4)1k (23)
i-Pr2NEt (2.6)1k (13)
DBU (1.1)1k (13)
DBN (0.5)1k (traces)
The highest yields of N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-2-amine (1a) and N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine (1g), 73 and 57%, respectively, were obtained with Hünig’s base, while the highest yield for N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-4-amine (1k) (23%) was obtained with Et3N. The exceptionally low yields of product from the reaction of 4-aminopyridine and Appel salt 4 may be partially explained by the reduced nucleophilicity of the primary amine, which is due to a significant contribution of a zwitterionic resonance form. This deactivation is not observed with 2-aminopyridine since the contribution of the analogous zwitterionic resonance form is considerably less important (Scheme 2) [28]. Moreover, 4-aminopyridine was not very soluble in the solvents tried (DCM, PhH, MeOH, EtOH,) and this could also have contributed to the low product yields.
Molecules 16 08992 g003 550
Scheme 2. Zwitterionic resonance forms for 2- and 4-aminopyridines.
Scheme 2. Zwitterionic resonance forms for 2- and 4-aminopyridines.
Molecules 16 08992 g003
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).
Molecules 16 08992 g004 550
Scheme 3. Proposed intermediates for the synthesis of (dithiazolylidene)pyridin-2-amine 7.
Scheme 3. Proposed intermediates for the synthesis of (dithiazolylidene)pyridin-2-amine 7.
Molecules 16 08992 g004

2.2. 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 NO2) 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%).
Table
Table 2. Reaction of 4,5-dichloro-1,2,3-dithiazolium chloride 4 (2.18 mmol) with aminoazines (2.18 mmol) in DCM (4 mL) at ca. 20 °C for 1 h and then addition of base (4.36 mmol) for 2 h to give [(4-chloro-5H-1,2,3-dithiazolylidene)amino]azines 1a–m.
Table 2. Reaction of 4,5-dichloro-1,2,3-dithiazolium chloride 4 (2.18 mmol) with aminoazines (2.18 mmol) in DCM (4 mL) at ca. 20 °C for 1 h and then addition of base (4.36 mmol) for 2 h to give [(4-chloro-5H-1,2,3-dithiazolylidene)amino]azines 1a–m.
AzineProduct Yields (%)
PyridineLutidineDABCOEt3Ni-Pr2NEtDBUDBN
1a (pyrid-2-yl)69725569735847
1b (3-MeO-pyrid-2-yl)71675560664240
1c (3,5-Cl2-pyrid-2-yl)69705244434439
1d (3,5-Br2-pyrid-2-yl)65705648402715
1e (3-O2N-pyrid-2-yl)45624832142312
1f (pyrazin-2-yl)65635163614036
1g (pyrid-3-yl)2345842571610
1h (2-HO-pyrid-3-yl)531911918125
1i (2-Cl-pyrid-3-yl)75828571725045
1j (4-Cl-pyrid-3-yl)65766070692119
1k (pyrid-4-yl)tracetrace321131310
1l (2,6-Me2-pyrid-4-yl)5trace19221095
1m (5-NC-pyrimid-4-yl)61553545403915

3. Experimental

3.1. General

Reactions were protected from atmospheric moisture by CaCl2 drying tubes. Anhydrous Na2SO4 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 F254). 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. 1H- and 13C-NMR spectra were recorded on a Bruker Avance 300 instrument (at 300 and 75 MHz, respectively). 13C-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.

3.2. General Procedure for the Synthesis of [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines

To a stirred solution of 4,5-dichloro-1,2,3-dithiazolium chloride (4, 454.2 mg, 2.18 mmol) in DCM (4 mL) at ca. 20 °C and protected with CaCl2 drying tube, was added the corresponding aminoazine (1 equiv., 2.18 mmol). After 1 h, to the reaction mixture was added, dropwise, the appropriate base (2 equiv., 4.36 mmol) and the mixture left to stir at ca. 20 °C for additional 2 h. The reaction mixture was subsequently adsorbed onto silica and chromatographed to afford the corresponding [(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azine 1.
(Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-2-amine (1a): Yellow-green needles (365.6 mg, 73%), mp 149–150 °C (lit. [24], 154–155 °C) (cyclohexane); Anal. found: C, 36.6; H, 1.7; N, 18.3. C7H4ClN3S2 requires C, 36.6; H, 1.8; N, 18.3%); UV λmax(DCM)/nm 246 (log ε 2.83), 294 (2.48), 388 (2.84), 405 (2.96), 427 (2.76); IR vmax/cm−11589w, 1560w, 1512m, 1491m, 1449m, 1431m, 1296w, 1267w, 1258w, 1175m, 1142m, 1092w, 1042w, 999w, 891m, 862m, 787s, 742m, 704m; 1H-NMR (CDCl3) δH 8.60 (1H, d, J 4.2, H-3 or 6), 7.90 (1H, ddd, 7.7, 7.7, 1.7, H-4 or 5), 7.67 (1H, d, J 8.1, H-3 or 6), 7.28 (1H, ddd, J 7.2, 5.1, 1.0, H-4 or 5); 13C-NMR (CDCl3) δC 157.9 (s), 153.9 (s), 148.9 (s), 143.3 (d), 138.4 (d), 122.4 (d), 121.6 (d); MS m/z (EI) 231 (M++2, 8%), 229 (M+, 19), 194 (85), 168 (5), 162 (5), 125 (3), 104 (3), 78 (100), 70 (6), 64 (20), 51 (43).
(Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-methoxypyridin-2-amine (1b): Yellow fibers (402 mg, 71%), mp 190–191 °C (cyclohexane/EtOH); Anal. found: C, 36.9; H, 2.1; N, 16.3. C8H6ClN3OS2 requires C, 37.0; H, 2.3; N, 16.2%); UV λmax(DCM) 228 (log ε 3.69), 249 (3.70), 304 (3.42), 361 inf (3.05), 374 inf (3.33), 386 inf (3.53), 403 (3.78), 425 (3.85), 449 (3.61); IR vmax/cm−1 3075w, 2970w, 2936w, 2837w, 1572m, 1508m, 1487m, 1464m, 1449w, 1431s, 1425s, 1308s, 1294m, 1279s, 1263w, 1209w, 1182m, 1171m, 1155w, 1125s, 1076w, 1013s, 951w, 893m, 868s, 808s, 783s, 773w, 764s; 1H-NMR (DMSO-d6) δH 8.22 (1H, d, J 4.2, H-4 or 6), 7.63 (1H, d, J 7.8, H-4 or 6), 7.43 (1H, dd, J 8.1, 4.8, H-5), 3.95 (3H, s, CH3O); 13C-NMR (DMSO-d6) δC156.9 (s), 150.6 (s), 148.3 (s), 144.3 (s), 134.3 (d), 123.3 (d), 119.8 (d), 55.9 (CH3O); MS m/z (EI); 261 (M++2, 8%), 259 (M+, 19), 226 (8), 224 (37), 195 (5), 160 (36), 134 (7), 123 (8), 108 (13), 93 (14), 78 (100), 70 (12), 64 (30), 51 (20).
(Z)-3,5-Dichloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-2-amine (1c): Yellow cotton fibers (456 mg, 70%), mp 145–146 °C (from cyclohexane); Anal. found: C, 28.2; H, 0.6; N, 13.9. C7H2Cl3N3S2 requires C, 28.2; H, 0.7; N, 14.1%); UV λmax (DCM) 229 (log ε 3.17), 254 (3.30), 261 (3.26), 313 (2.86), 338 inf (3.07), 397 (3.31), 418 (3.42), 440 (3.22); IR vmax/cm−1 3067w, 3049w (Ar CH), 1564m, 1539m, 1524m, 1491m, 1412s, 1377m, 1279m, 1240m, 1225w, 1171m, 1142w, 1121m, 1061m, 924w, 901m, 880s, 810m, 764m, 756m; 1H-NMR (DMSO-d6) δH 8.64 (1H, d, J 2.2, H-4 or 6), 8.37 (1H, d, J 2.2, H-4 or 6); 13C-NMR (DMSO-d6) δC 160.3 (s), 150.1 (s), 148.6 (s), 141.6 (d), 138.4 (d), 127.6 (s), 127.5 (s); MS m/z (EI); 301 (M++4, 3%) 299 (M++2, 6), 297 (M+, 6), 266 (4), 264 (18), 262 (24), 236 (3), 172 (3), 146 (10), 137 (4), 125 (4), 110 (29), 102 (5), 98 (5), 93 (8), 85 (8), 75 (15), 70 (16), 64 (100), 50 (5).
(Z)-3,5-Dibromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-2-amine (1d): Yellow cubes (591 mg, 70%), mp 174–175 °C (from cyclohexane); Anal. found: C, 21.8; H, 0.5; N, 10.8. C7H2Br2ClN3S2 requires C, 21.7; H, 0.5; N, 10.8%); UV λmax (DCM) 229 (log ε 3.08), 257 (3.16), 262 inf (3.11), 316 (2.69), 325 inf (2.59), 365 inf (2.52), 399 (3.16), 419 (3.27), 442 (3.07); UV vmax/cm−1 1539m, 1514m, 1485m, 1454w, 1414s, 1364m, 1314w, 1275m, 1244w, 1231w, 1167m, 1123w, 1098m, 1045m, 914w, 897m, 891m, 876s, 795s, 754m, 737s; 1H-NMR (DMSO-d6) δ H8.75 (1H, s, H-4 or 6), 8.59 (1H, s, H-4 or 6); 13C-NMR (DMSO-d6) δC 160.3 (s), 151.1 (s), 148.6 (s), 144.3 (d), 143.9 (d), 118.4 (s), 115.8 (s); MS m/z (EI); 391 (M++6, 4%), 389 (M++4, 18), 387 (M++2, 21), 385 (M+, 9), 354 (25), 352 (37), 350 (20), 310 (10), 308 (28), 306 (23), 262 (5), 247 (11), 245 (11), 238 (8), 236 (17), 234 (9), 183 (6), 181 (6), 156 (21), 154 (19), 125 (7), 102 (12), 93 (9), 76 (41), 64 (100), 50 (15).
(Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-3-nitropyridin-2-amine (1e): Yellow cotton fibers (371 mg, 62%), mp 188–189 °C (from cyclohexane); Anal. found: C, 30.7; H, 1.0; N, 20.4. C7H3ClN4O2S2 requires C, 30.6; H, 1.1; N, 20.4%); UV λmax(DCM)/nm 230 (log ε 2.93), 278 (2.49), 395 inf (2.90), 411 (3.03), 432 (2.88); IR vmax/cm−1 1597m, 1560m, 1526s, 1479m, 1427s, 1362m, 1344s, 1279w, 1261w, 1244w, 1169m, 1086w, 901s, 878m, 847s, 808s, 770s, 706m; 1H-NMR (DMSO-d6) δH 8.87 (1H, dd, J 5.0, 1.5, H-6), 8.53 (1H, dd, J 7.9, 1.5, H-4), 7.59 (1H, dd, J 7.9, 5.0, H-5); 13C-NMR (DMSO-d6) δC 161.9 (s), 148.6 (s), 148.3 (d), 146.8 (s), 141.6 (s), 133.5 (d), 121.8 (d); MS m/z (EI); 276 (M++2, 16%), 274 (M+, 37), 239 (18), 228 (41), 226 (99), 210 (4), 191 (6), 155 (12), 149 (35), 137 (13), 119 (78), 102 (18), 91 (63), 76 (38), 70 (29), 64 (100), 50 (22).
(Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)pyrazin-2-amine (1f): Yellow-orange needles (327 mg, 65%), mp 208–209 °C (from cyclohexane/EtOH); Anal. found: C, 31.2; H, 1.2; N, 24.2. C6H3ClN4S2 requires C, 31.2; H, 1.3; N, 24.3%); UV λmax(DCM) 230 (log ε 3.02), 243 (3.02), 252 inf (2.96), 297 (2.72), 322 inf (2.61), 379 inf (2.89), 392 (3.10), 409 (3.23), 430 (3.06); IR vmax/cm−1 1526s, 1501m, 1476s, 1452s, 1406s, 1298m, 1281m, 1179s, 1146m, 1061m, 1016m, 903s, 868s, 845s, 793s, 750w, 714m; 1H-NMR (DMSO-d6) δH 8.95 (1H, d, J 1.2, H-3), 8.72 (1H, dd, J 2.7, 1.5, H-5), 8.59 (1H, d, J 2.7, H-6); 13C-NMR (DMSO-d6) δC 160.6 (s), 150.6 (s), 148.5 (s), 144.7 (d), 141.0 (d), 139.3 (d); MS m/z (EI) 232 (M++2, 14%), 230 (M+, 32), 195 (100), 169 (11), 125 (12), 102 (8), 93 (6), 84 (6), 79 (70), 70 (16), 64 (68), 52 (66).
(Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine (1g): Yellow cotton fibers (285 mg, 57%), mp 126–127 °C (from cyclohexane/EtOH); Anal. found: C, 36.7; H, 1.7; N, 18.2. C7H4ClN3S2 requires C, 36.6; H, 1.8; N, 18.3%); UV λmax (DCM) 231 (log ε 2.86), 280 (2.33), 374 (2.65); IR vmax/cm−1 3051w, 3042w, 1570s, 1539w, 1504m, 1474m, 1410s, 1327w, 1229s, 1192m, 1150s, 1121w, 1099m, 1042m, 1022m, 943m, 914m, 870s, 851m, 812m, 773s, 706s; 1H-NMR (DMSO-d6) δH 8.47–8.43 (2H, m, H-2 and 6), 7.65 (1H, ddd, J 8.3, 2.6, 1.5, H-4), 7.51 (1H, dd, J 8.1, 4.8, H-5); 13C-NMR (DMSO-d6) δC 161.9 (s), 147.3 (s), 146.8 (d), 146.6 (s), 141.5 (d), 126.3 (d), 124.6 (d); MS m/z (EI) 231 (M++2, 17%), 229 (M+, 42), 168 (23), 130 (6), 125 (8), 104 (9), 102 (5), 93 (6), 78 (38), 70 (11), 64 (S2, 100), 51 (47).
(Z)-3-(4-Chloro-5H-1,2,3-dithiazol-5-ylideneamino)pyridin-2-ol (1h): Orange dust (284 mg, 53%), mp 151–152 °C (from pentane/DCM); Anal. found C, 34.3; H, 1.7; N, 17.0. C7H4ClN3OS2 requires C, 34.2; H, 1.6; N, 17.1%); UV λmax (DCM)/nm 228 (log ε 2.75), 251 (2.67), 326 (2.64), 347 (2.64), 409 (2.77); IR vmax/cm−1 3125w (OH), 2922w, 2853w, 1638s, 1612m, 1572m, 1547m, 1524w, 1472m, 1433w, 1358w, 1346w, 1323w, 1310w, 1245m, 1236m, 1175w, 1144m, 1057w, 1020w, 959w, 943m, 910m, 893w, 858s, 826w, 797w, 779w, 770s; 1H-NMR (DMSO-d6) δH 12.07 (1H, br s, OH), 7.37–7.34 (2H, m, Py H), 6.33 (1H, dd, J 6.7, 6.7, Py H); 13C-NMR (DMSO-d6) δC 157.5 (s), 155.1 (s), 147.0 (s), 137.9 (s), 132.7 (d), 131.2 (d), 105.6 (d); MS m/z (EI) 247 (M++2, 9%), 245 (M+, 21), 210 (32), 146 (100), 135 (9), 120 (13), 117 (10), 102 (12), 92 (40), 76 (11), 70 (33), 64 (77), 52 (19).
(Z)-2-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine (1i): Yellow-orange needles (489.5 mg, 85%), mp 133–134 °C (from cyclohexane); Anal. found: C, 31.9; H, 1.0; N, 15.9. C7H3Cl2N3S2 requires C, 31.8; H, 1.1; N, 15.9%); UV λmax (DCM) 232 (log ε 2.87), 281 (2.46), 363 (2.63); IR vmax/cm−1 3051w, 1722w, 1703w, 1657w, 1584s, 1566w, 1557w, 1506m, 1443w, 1400s, 1267w, 1250w, 1240w, 1207m, 1157m, 1082s, 1067w, 972w, 926w, 903w, 870s, 797m, 779s, 743s, 710s; 1H-NMR (CDCl3) δH 8.26 (1H, d, J 3.6, H-6), 7.45 (1H, dd, J 7.7, 1.3, H-4), 7.33 (1H, dd, J 7.8, 4.7, H-5); 13C-NMR (CDCl3) δC 162.8 (s), 147.3 (s), 146.4 (d), 145.0 (s), 142.5 (s), 127.3 (d), 123.4 (d); MS m/z (EI); 267 (M++4, 4%), 265 (M++2, 21), 263 (M+, 30), 204 (14), 202 (34), 164 (9), 135 (6), 125 (7), 112 (13), 103 (14), 93 (7), 76 (30), 70 (10), 64 (100), 50 (14).
(Z)-4-Chloro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-3-amine (1j): Yellow prisms (437.6 mg, 76%), mp 160–161 °C (from cyclohexane/EtOH); Anal. found: C, 31.9; H, 1.1; N, 15.8. C7H3Cl2N3S2 requires C, 31.8; H, 1.1; N, 15.9%); UV λmax (DCM) 231 (log ε 2.80), 279 (2.32), 364 (2.59); IR vmax/cm−1 3080w, 3057w, 1591s, 1557m, 1547w, 1506m, 1485w, 1466m, 1402m, 1283m, 1242m, 1225w, 1215w, 1146m, 1092s, 1053w, 966w, 912m, 862s, 831s, 783s, 739w, 708s; 1H-NMR (DMSO-d6) δH 8.48 (1H, s, H-2), 8.40 (1H, d, J 5.4, H-5 or 6), 7.70 (1H, d, J 5.4, H-5 or 6); 13C-NMR (DMSO-d6) δC 164.5 (s), 147.4 (d), 145.7 (s), 145.6 (s), 140.6 (d), 133.4 (s), 125.1 (d); MS m/z (EI) 267 (M++4, 3%), 265 (M++2, 20), 263 (M+, 26), 204 (9), 202 (21), 170 (3), 164 (3), 138 (3), 125 (7), 112 (12), 103 (9), 93 (5), 85 (12), 76 (18), 70 (7), 64 (100), 50 (15).
(Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)pyridin-4-amine (1k): Yellow prisms (120 mg, 24%), mp 166–167 °C (from cyclohexane/EtOH); Anal. found: C, 36.5; H, 1.8; N, 18.1. C7H4ClN3S2 requires C, 36.6; H, 1.8; N, 18.3%); UV λmax (DCM) 230 (log ε 2.82), 374 (2.63); IR vmax/cm−1 1593m, 1568s, 1549m, 1501m, 1485w, 1418m, 1246w, 1207m, 1152m, 1090w, 1053w, 999m, 872s, 858s, 827m, 779m, 735w; 1H-NMR (DMSO-d6) δH 8.63 (2H, d, J 5.1, H-2 and 6), 7.15 (2H, dd, J 4.7, 1.4, H-3 and 5); 13C-NMR (DMSO-d6) δC 162.5 (s), 158.1 (s), 151.6 (d), 146.4 (s), 113.9 (d); MS m/z (EI) 231 (M++2, 34%), 229 (M+, 87), 194 (25), 168 (57), 162 (24), 130 (14), 127 (13), 125 (31), 104 (14), 93 (11), 78 (55), 64 (100), 51 (70).
(Z)-N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-2,6-dimethylpyridin-4-amine (1l): Yellow prisms (124 mg, 22%), mp 127–128 °C (from cyclohexane/EtOH); Anal. found: C, 42.0; H, 3.1; N, 16.3. C9H8ClN3S2 requires C, 41.9; H, 3.1; N, 16.3%); UV λmax (DCM) 331 (log ε 3.01), 248 inf (2.72), 317 inf (2.28), 370 (2.75); IR vmax/cm−1 2920w, 1645w, 1584s, 1557m, 1508m, 1454w, 1410w, 1373w, 1319m, 1292w, 1269w, 1238w. 1207w, 1171s, 1123w, 1024w, 995w, 939m, 887s, 864w, 839m, 779s, 756w, 733m; 1H-NMR (CDCl3) δH 6.65 (2H, s, H-2 and 6), 2.50 (6H, s, 2 × CH3); 13C-NMR (CDCl3) δC 160.8 (s), 160.0 (s), 159.0 (s), 147.4 (s), 109.8 (d), 24.5 (CH3); MS m/z (EI) 259 (M++2, 36%), 257 (M+, 84), 244 (5), 242 (20), 224 (12), 222 (38), 196 (14), 190 (31), 132 (100), 125 (13), 106 (25), 91 (6), 77 (7), 64 (51), 51 (6).
(Z)-4-[(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]pyrimidine-5-carbonitrile (1m): Orange prisms (340 mg, 61%), mp 205–206 °C (from EtOH); Anal. found: C, 32.9; H, 0.8; N, 27.3. C7H2ClN5S2 requires C, 32.9; H, 0.8; N, 27.4%); UV λmax (DCM) 230 (log ε 2.70), 268 (2.57), 318 inf (2.06), 376 inf (2.50), 395 (2.88), 414 (3.08), 435 (2.99); IR vmax/cm−1 2239w and 2230w (C≡N), 1565w, 1560w, 1537m, 1507m, 1459s, 1424s, 1412s, 1391s, 1282w, 1192m, 1178w, 1162w, 1106w, 950w, 923s, 876s, 823w, 816m, 787m, 774m; 1H-NMR (acetone-d6) δH 9.45 (1H, s, H-2 or 6), 9.28 (1H, s, H-2 or 6); 13C-NMR (acetone-d6) δC 166.4 (s), 163.1 (d), 162.3 (s), 159.2 (d), 150.9 (s), 114.6 (C≡N), 105.6 (CC≡N); MS m/z (EI) 257 (M++2, 12%), 255 (M+, 27), 220 (87), 194 (9), 125 (10), 104 (11), 102 (8), 93 (8), 77 (55), 70 (12), 64 (100), 51 (17).

4. Conclusions

The reaction conditions for the synthesis of a series of [(4-chloro-5H-1,2,3-dithiazolyl-idene)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 Et3N and Hünig’s base often gave superior product yields.

Acknowledgments

The authors wish to thank the Cyprus Research Promotion Foundation [Grant Nos. NEAYΠΟΔΟΜΗ/ΝΕΚΥΠ/0308/02 and TEXNOΛOΓIA/ΘEΠΙΣ/0308(BE)/08] and the following organizations in Cyprus for generous donations of chemicals and glassware: the State General Laboratory, the Agricultural Research Institute, the Ministry of Agriculture and Biotronics Ltd. Furthermore, we thank the A.G. Leventis Foundation for helping to establish the NMR facility in the University of Cyprus.

References

  1. Konstantinova, L.S.; Bol’shakov, O.I.; Obruchnikova, N.V.; Laborie, H.; Tanga, A.; Sopéna, V.; Lanneluc, I.; Picot, L.; Sablé, S.; Thiéry, V.; Rakitin, O.A. One-pot synthesis of 5-phenylimino, 5-thieno or 5-oxo-1,2,3-dithiazoles and evaluation of their antimicrobial and antitumor activity. Bioorg. Med. Chem. Lett. 2009, 19, 136–141. [Google Scholar]
  2. Cottenceau, G.; Besson, T.; Gautier, V.; Rees, C.W.; Pons, A.M. Antibacterial evaluation of novel N-arylimino-1,2,3-dithiazoles and N-arylcyanothioformamides. Bioorg. Med. Chem. Lett. 1996, 6, 529–532. [Google Scholar] [CrossRef]
  3. Thiery, V.; Rees, C.W.; Besson, T.; Cottenceau, G.; Pons, A.M. Antimicrobial activity of novel N-quinolinyl and N-naphthylimino-1,2,3-dithiazoles. Eur. J. Med. Chem. 1998, 33, 149–153. [Google Scholar]
  4. Joseph, R.W.; Antes, D.L.; Osei-Gyimah, P. Antimicrobial Compounds with Quick Speed of Kill. US Patent 5688744, 1997. [Google Scholar]
  5. Moore, J.E. Certain 4-Halo-5-aryl-1,2,3-dithiazole Compounds and their Preparation. US Patent 4059590, 1977. [Google Scholar]
  6. Appel, R.; Janssen, H.; Haller, I.; Plempel, M. 1,2,3-Dithiazolderivate, Verfahren zu ihrer Herstellung Sowie ihre Verwendung als Arzneimittel. DE Patent 2848221, 1980. [Google Scholar]
  7. Besson, T.; Rees, C.W.; Cottenceau, G.; Pons, A.M. Antimicrobial evaluation of 3,1-benzoxazin-4-ones, 3,1-benzothiazin-4-ones, 4-alkoxyquinazolin-2-carbonitriles and N-arylimino-1,2,3-dithiazoles. Bioorg. Med. Chem. Lett. 1996, 6, 2343–2348. [Google Scholar] [CrossRef]
  8. Mayer, R.; Foerster, E.; Matauschek, B. Verfahren zur Herstellung von Aromatisch oder Heteroaromatisch Substituierten Cyanthioformamiden. DD Patent 212387 1984. [Google Scholar]
  9. Konstantinova, L.S.; Rakitin, O.A. Synthesis and properties of 1,2,3-dithiazoles. Russ. Chem. Rev. 2008, 77, 521–546. [Google Scholar] [CrossRef]
  10. Rees, C.W. Polysulfur-nitrogen heterocyclic chemistry. J. Heterocycl. Chem. 1992, 29, 639–651. [Google Scholar] [CrossRef]
  11. Besson, T.; Dozias, M.J.; Guillard, J.; Rees, C.W. New route to 2-Cyano-benzothiazoles via N-Arylimino-1,2,3-dithiazoles. J. Chem. Soc., Perkin Trans. 1 1998, 3925–3926. [Google Scholar]
  12. Rakitin, O.A.; Rees, C.W.; Vlasova, O.G. Direct synthesis of 2-Cyano-benzimidazoles and the generation of S2. Tetrahedron Lett. 1996, 37, 4589–4592. [Google Scholar] [CrossRef]
  13. Christoforou, I.C.; Koutentis, P.A.; Michaelidou, S.S. 1,2,3-Dithiazole chemistry in heterocyclic synthesis. ARKIVOC 2006, 7, 207–223. [Google Scholar]
  14. Besson, T.; Guillaumet, G.; Lamazzi, C.; Rees, C.W. Synthesis of 3,1-benzoxazines, 3,1-benzothiazines and 3,1-benzoxazepines via N-arylimino-1,2,3-dithiazoles. Synlett 1997, 704–706. [Google Scholar]
  15. Lee, H.; Kim, K. A new procedure to N-arylcyanothioformamides from 5-arylimino-4-chloro-5H-1,2,3-dithiazoles. Bull. Korean Chem. Soc. 1992, 13, 107–108. [Google Scholar]
  16. Michaelidou, S.S.; Koutentis, P.A. The synthesis of 2-cyano cyanothioformanilides from 2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzonitriles using DBU. Synthesis 2009, 4167–4174. [Google Scholar]
  17. Besson, T.; Emayan, K.; Rees, C.W. 1,2,3-Dithiazoles and new routes to 3,1-benzoxazin-4-ones, 3,1-benzothiazin-4-ones and N-arylcyanothioformamides. J. Chem. Soc. Perkin Trans. 1 1995, 2097–2102. [Google Scholar]
  18. Lee, H.; Kim, K. Reactions of 5-(arylimino)-4-chloro-5H-1,2,3-dithiazoles with primary and secondary alkylamines: Novel synthesis of (arylimino)cyanomethyl alkylamino disulfides and their mechanisms of formation. J. Org. Chem. 1993, 58, 7001–7008. [Google Scholar] [CrossRef]
  19. Besson, T.; Guillard, J.; Rees, C.W. Rapid synthesis of 2-cyanobenzothiazole, isothiocyanates and cyanoformanilide derivatives of dapsone. J. Chem. Soc. Perkin Trans. 1 2000, 563–566. [Google Scholar]
  20. Besson, T.; Guillard, J.; Rees, C.W.; Thiéry, V. New syntheses of aryl isothiocyanates. J. Chem. Soc. Perkin Trans. 1 1998, 889–892. [Google Scholar]
  21. Baraldi, P.G.; Pavani, M.G.; Nuñez, M.C.; Brigidi, P.; Vitali, B.; Gambari, R.; Romagnoli, R. Antimicrobial and antitumor activity of n-heteroimmine-1,2,3-dithiazoles and their transformation in triazolo-, imidazo-, and pyrazolopirimidines. Bioorg. Med. Chem. 2002, 10, 449–456. [Google Scholar] [CrossRef]
  22. Lee, H.-S.; Chang, Y.-G.; Kim, K. A facile synthesis of 3-substituted 2-cyanoquinazolin-4(3H)-ones and 3-alkyl-2-cyanothieno[3,2-d]pyrimidin-4(3H)-ones via 1,2,3-dithiazoles. J. Heterocycl. Chem. 1998, 35, 659–668. [Google Scholar] [CrossRef]
  23. Cuadro, A.M.; Alvarez-Builla, J. 4,5-Dichloro-1,2,3-dithiazolium chloride (Appel’s Salt): reactions with N-nucleophiles. Tetrahedron 1994, 50, 10037–10046. [Google Scholar] [CrossRef]
  24. English, R.F.; Rakitin, O.A.; Rees, C.W.; Vlasova, O.G. Conversion of imino-1,2,3-dithiazoles into 2-cyanobenzothiazoles, cyanoimidoyl chlorides and diatomic sulfur. J. Chem. Soc. Perkin Trans. 1 1997, 201–205. [Google Scholar]
  25. Konstandinova, L.S.; Rakitin, O.A.; Rees, C.W.; Sivadasan, S.; Torrobas, T. New route to 2-cyanobenzimidazoles. Tetrahedron 1998, 54, 9639–9650. [Google Scholar] [CrossRef]
  26. Kalogirou, A.S.; Koutentis, P.A. The degradation of 4,5-dichloro-1,2,3-dithiazolium chloride in wet solvents. Tetrahedron 2009, 65, 6859–6862. [Google Scholar] [CrossRef]
  27. Bordwell pKa Table (Acidity in DMSO). Available online: http://www.chem.wisc.edu/areas/reich/pkatable/ accessed on 1 June 2011.
  28. Stewart, R.; Harris, M.G. Comparison of the acidities and basicities of amino-substituted nitrogen heterocycles. J. Org. Chem. 1978, 43, 3123–3126. [Google Scholar] [CrossRef]
  29. L’abbe, G.; D’hooge, B.; Dehaen, W. Unusual behavior of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) with 5-aminopyrazoles: A synthetic method of 1H-pyrazolo[3,4-d]-thiazoles. J. Chem. Soc., Perkin Trans. 1 1995, 2379–2380. [Google Scholar]
  30. L’abbe, G.; Bastin, L.; Dehaen, W.; Toppet, S.; Delbeke, P.; Vlieghe, D.; van Meerveek, L. Reactions of 5-chloro-1,2,3-dithiazolium salts with activated methylene compounds. J. Chem. Soc., Perkin Trans. 1 1994, 2545–2551. [Google Scholar]
  • Samples Availability: Samples of the compounds are available from the authors.

Share and Cite

MDPI and ACS Style

Koutentis, P.A.; Koyioni, M.; Michaelidou, S.S. Synthesis of [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines. Molecules 2011, 16, 8992-9002. https://doi.org/10.3390/molecules16118992

AMA Style

Koutentis PA, Koyioni M, Michaelidou SS. Synthesis of [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines. Molecules. 2011; 16(11):8992-9002. https://doi.org/10.3390/molecules16118992

Chicago/Turabian Style

Koutentis, Panayiotis A., Maria Koyioni, and Sophia S. Michaelidou. 2011. "Synthesis of [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines" Molecules 16, no. 11: 8992-9002. https://doi.org/10.3390/molecules16118992

APA Style

Koutentis, P. A., Koyioni, M., & Michaelidou, S. S. (2011). Synthesis of [(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino]azines. Molecules, 16(11), 8992-9002. https://doi.org/10.3390/molecules16118992

Article Metrics

Back to TopTop