Next Article in Journal
Steroidal Lactones from Withania somnifera, an Ancient Plant for Novel Medicine
Next Article in Special Issue
Synthesis, ex Vivo and in Vitro Hydrolysis Study of an Indoline Derivative Designed as an Anti-Inflammatory with Reduced Gastric Ulceration Properties
Previous Article in Journal
Salivary Aldehyde Dehydrogenase: Activity towards Aromatic Aldehydes and Comparison with Recombinant ALDH3A1
Article Menu

Export Article

Molecules 2009, 14(7), 2356-2362; doi:10.3390/molecules14072356

Article
The Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride with Sulfimides: A New Synthesis of N-Aryl-1,2,3-dithiazolimines
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
*
Author to whom correspondence should be addressed.
Received: 26 May 2009; in revised form: 10 June 2009 / Accepted: 12 June 2009 / Published: 2 July 2009

Abstract

:
N-Aryl-S,S-dimethylsulfimides 3 (Ar = 4-NO2C6H4), 4 (Ar = Ph) and 5 (Ar = 4-Tol) react with Appel salt 1 to give the corresponding N-aryl-(4-chloro-5H-1,2,3-dithiazolylidene)benzenamines 8 (Ar = 4-NO2C6H4), 9 (Ar = Ph) and 10 (Ar = 4-Tol) in 84, 94 and 87% yields, respectively. The reaction proceeds in the absence of base and a proposed reaction mechanism is given.
Keywords:
dithiazole; dithiazolimine; sulfimide; sulfilimine; heteroarene; appel salt

1. Introduction

N-Aryl-1,2,3-dithiazol-5H-imines show interesting antitumour [1], antibacterial [2,3,4], antifungal [5,6,7], and herbicidal [8] activities. The biological activity could be due to the 1,2,3-dithiazole ring, which acts as a powerful inhibitor of several enzymes that are structurally related to serine proteases [9]. Furthermore N-aryldithiazolimines are useful precursors to other heterocycles through ANRORC [10,11] style ring transformations. For example the thermolysis of N-aryldithiazolimines can afford benzothiazoles [12,13], benzimidazoles [14], thiazolopyridines [15] and benzoxazines [16].
Most primary arylamines react readily with 4,5-dichloro-1,2,3-dithiazolium chloride 1 (Appel salt) [9,17,18,19] to give, after treatment with tertiary amine base (2 equiv.), the corresponding N-aryl-4-chloro-5H-1,2,3-dithiazolimines 2 in good to excellent yields [20,21] (Scheme 1). In some cases, such as with arylamides [22], heteroarylamines [21,23] or alkylamines [20,21], the reactions are low yielding or complex. As such this simple condensation reaction has room for improvement.
Scheme 1. The classical reaction of anilines with Appel salt 1 to afford dithiazolimines 2.
Scheme 1. The classical reaction of anilines with Appel salt 1 to afford dithiazolimines 2.
Molecules 14 02356 g001
Sulfimides act as transfer reagents in the form of an “activated amine”. For example sulfimides react with nitrile oxides to afford 1H-l,2,4-triazole 2-oxides [24], and react with alkoxychromium (Fischer) carbenes to form imidates [25]. In view of their use as N-transfer reagents to electrophiles, we examined an alternative route to N-aryl-1,2,3-dithiazolimines by reacting N-aryl-S,S-dimethyl-sulfimides with Appel salt 1.

2. Results and Discussion

We were able to prepare five sulfimides according to literature procedures (3, R = 4-NO2C6H4 [26]; 4, R = Ph [26]; 5, R = 4-Tol [26]; 6, R = Pyrid-2-yl [27]; and 7, R = Bz [26]). Disappointingly, treating Appel salt 1 with either the N-pyrid-2-yl or N-benzoyl sulfimides 6 and 7 (1 equiv.) in DCM (dry) at ca. 20 oC gave only complex reaction mixtures (by TLC) that were not investigated further. Nevertheless the three N-aryl-sulfimides 3-5 reacted rapidly with Appel salt 1 to give the anticipated N-aryl-(4-chloro-5H-1,2,3-dithiazol-5-imines) 8-10 in excellent yields (84, 94 and 87%, respectively), comparable to those obtained in our hands from the classical [21] condensation of Appel salt 1 with the corresponding aniline (1 equiv.) and pyridine (2 equiv.) (Table 1).
Table 1. Reaction of Appel salt 1 (0.96 mmol) with: sulfimides (Method A) and anilines (Method B), in dry DCM, at ca. 20 °C.
Table 1. Reaction of Appel salt 1 (0.96 mmol) with: sulfimides (Method A) and anilines (Method B), in dry DCM, at ca. 20 °C.
Molecules 14 02356 i001
Repeating the reaction of the N-(4-nitrophenyl)sulfimide 3 with Appel salt 1 in dry MeCN at ca. 20 oC gave marginally lower yields of the dithiazolimine 8 (79%). A tentative mechanism for these reactions is proposed (Scheme 2).
Scheme 2. Proposed reaction mechanism for the reaction of sulfimide with 4,5-dichloro-1,2,3-dithiazolium chloride 1.
Scheme 2. Proposed reaction mechanism for the reaction of sulfimide with 4,5-dichloro-1,2,3-dithiazolium chloride 1.
Molecules 14 02356 g002
The N-aryl-S,S-dimethylsulfimide can attack Appel salt 1 at the highly electrophilic C-5 position to afford, after elimination of chloride, a new dithiazolium intermediate 11 (Scheme 2). The cationic dimethylsulfonium can depart assisted by chloride or an equivalent species. The proposed chlorodimethylsulfonium chloride 12 byproduct was a well known species and under the reaction conditions can convert into a number of alternative species including DMSO on hydrolysis [28] or dimethylsulfide [29,30] on reductive dechlorination.
It is worth noting however, that while the reaction of Appel salt 1 with N-aryl-S,S-dimethylsulfimides provides an alternative, mild and fast route to dithiazolimines in the absence of base, it has drawbacks owing to the limited availability of a wide range of sulfimide reagents [26,27,31].

3. Conclusions

N-Aryl-S,S-dimethylsulfimides 3 (Ar = 4-NO2C6H4), 4 (Ar = Ph) and 5 (Ar = 4-Tol) react with Appel salt 1 to give the corresponding N-aryl-(4-chloro-5H-1,2,3-dithiazolylidene)benzenamines 8 (Ar = 4-NO2C6H4), 9 (Ar = Ph) and 10 (Ar = 4-Tol) in 84, 94 and 87% yields, respectively. The reaction demonstrates an alternative and mild route to 1,2,3-dithiazolimines which does not require the addition of base (2 equiv.), but it is synthetically limited owing to the poor availability and stability of the required sulfimide reagents.

4. Experimental

4.1. General

Solvents DCM and MeCN were freshly distilled from CaH2 under argon. 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 machine (at 300 and 75 MHz, 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 GCMS with direct inlet probe. 4,5-Dichloro-1,2,3-dithiazolium chloride 1 [20], S,S-dimethyl-N-(4-nitrophenyl)-sulfimide 3 [26], S,S-dimethyl-N-phenylsulfimide 4 [26], S,S-dimethyl-N-(4-tolyl)sulfimide 5 [26], S,S-dimethyl-N-(pyrid-2-yl)sulfimide 6 [27], andN-benzoyl-S,S-dimethylsulfimide 7 [26], were prepared according to literature procedures.

4.2. Reactions of Appel salt 1 with sulfimides: Typical procedure (see Table 1)

To a stirred solution of 4,5-dichloro-1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol) in dry DCM (10 ml) at ca. 20 oC, S,S-dimethyl-N-(4-nitrophenyl)sulfimide 3 (95.5 mg, 0.48 mmol) was added in one portion. After 2 h no 4,5-dichloro-1,2,3-dithiazolium chloride remained. The reaction mixture was adsorbed onto silica and chromatography (hexane–DCM, 1 : 1) gave N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-nitrobenzenamine 8 (110.1 mg, 84%) as yellow needles, mp 161-162 oC (lit. [5], 160 oC) (from cyclohexane) identical with an authentic sample.
N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)benzenamine 9: Similarly treatment of 4,5-dichloro-1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol) with S,S-dimethyl-N-phenylsulfimide 4 (73.4 mg, 0.48 mmol) gave the title compound 9 (103.1 mg, 94%) as yellow needles, mp 61-62 oC (lit. [5], 63-65 oC) (from cyclohexane) identical with an authentic sample.
N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylbenzenamine 10: Similarly treatment of compound 1 (100 mg, 0.48 mmol) with S,S-dimethyl-N-(4-tolyl)sulfimide 5 (80.1 mg, 0.48 mmol) gave the title compound 9 (101.9 mg, 87%) as yellow needles, mp 64-65 oC (lit. [5], 66-67 oC) (from cyclohexane) identical with an authentic sample.

4.3. Reactions of Appel salt 1 with anilines: Typical procedure [21] (see Table 1)

To a stirred solution of 4-nitroaniline (66.2 mg, 0.48 mmol) in DCM (2 ml) at ca. 20 oC, 4,5-dichloro-1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol) was added in one portion. After 2 h no Appel salt 1 remained and pyridine (80 μl, 0.96 mmol) was added. The mixture was stirred for additional 2 h and then adsorbed onto silica. Chromatography (light petroleum–DCM, 1 : 1) gave N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-nitrobenzenamine 8 (110.1 mg, 84%) as yellow needles, mp 161-162 oC (lit. [5], 160 oC) (from cyclohexane) identical to an authentic sample.
N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)benzenamine 9: Similarly treatment of aniline (43.8 μl, 0.48 mmol) with 4,5-dichloro-1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol) gave the title compound 9 (100.9 mg, 92%) as yellow needles, mp 61-62 oC (lit. [5], 63-65 oC) (from cyclohexane) identical to an authentic sample.
N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylbenzenamine 10: Similarly treatment of 4-methylaniline (51.4 mg, 0.48 mmol) with 4,5-dichloro-1,2,3-dithiazolium chloride 1 (100 mg, 0.48 mmol) gave the title compound 10 (111.3 mg, 95%) as yellow needles, mp 64-65 oC (lit. [5], 66-67 oC) (from cyclohexane) identical to an authentic sample.

Acknowledgements

The authors wish to thank the Cyprus Research Promotion Foundation [Grant No. NEAYΠΟΔΟΜΗ/ΝΕΚΥΠ/0308/02] and the following organisations in Cyprus for generous donations of chemicals and glassware: the State General Laboratory, the Agricultural Research Institute and the Ministry of Agriculture. Furthermore we thank the A.G. Leventis Foundation for helping to establish the NMR facility in the University of Cyprus.

References and Notes

  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] [CrossRef]
  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] [CrossRef]
  4. Joseph, R.W.; Antes, D.L.; Osei-Gyimah, P. Antimicrobial Compounds with Quick Speed of Kill. US Pat. 5688744.
  5. Moore, J.E. Certain 4-Halo-5-aryl-1,2,3-dithiazole Compounds and their Preparation. US Pat. 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 Pat. 2848221.
  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 Pat. 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]
  10. van der Plas, H.C. Chapter II SN(ANRORC) Reactions in Azines, Containing an “Outside” Leaving Group. Adv. Heterocycl. Chem. 1999, 74, 9–86. [Google Scholar]
  11. van der Plas, H.C. Chapter III SN(ANRORC) Reactions in Azaheterocycles Containing an “Inside” Leaving Group. Adv. Heterocycl. Chem. 1999, 74, 87–151. [Google Scholar]
  12. Rees, C.W. Polysulfur-nitrogen Heterocyclic Chemistry. J. Heterocycl. Chem. 1992, 29, 639–651. [Google Scholar] [CrossRef]
  13. 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]
  14. 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]
  15. Christoforou, I.C.; Koutentis, P.A.; Michaelidou, S.S. 1,2,3-Dithiazole Chemistry in Heterocyclic Synthesis. Arkivoc 2006, 7, 207–223. [Google Scholar]
  16. 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]
  17. Rakitin, O.A. Comprehensive Heterocyclic Chemistry, 3rd ed.; Zhdankin, V.V., Katritzky, A.R., Ramsden, C.A., Scriven, E.F.V., Taylor, R.J.K., Eds.; Elsevier: Oxford, UK, 2008; vol. 6, ch. 6.01; p. 1. [Google Scholar]
  18. Kim, K. Synthesis and Reactions of 1,2,3-Dithiazoles. J. Sulfur Chem. 1998, 21, 147–207. [Google Scholar]
  19. Kim, K. Recent Advances in 1,2,3-Dithiazole Chemistry. Phosphorus Sulfur Silicon Relat. Elem. 1997, 120, 229–244. [Google Scholar] [CrossRef]
  20. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Synthese und Reaktionen des 4,5-Dichlor-1,2,3-dithiazolium-chlorids. Chem. Ber. 1985, 118, 1632–1643. [Google Scholar] [CrossRef]
  21. 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, 201–206. [Google Scholar]
  22. English, R.F. Thesis, University of London, 1989.
  23. Cuadro, A.M.; Alvarez-Buila, 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. Gilchrist, T.L.; Harris, C.J.; Hawkins, D.G.; Moody, C.J.; Rees, C.W. Synthesis of 1H-1,2,4-Triazole 2-Oxides and Annelated Derivatives. J. Chem. Soc. Perkin Trans. 1 1976, 2166–2170. [Google Scholar]
  25. Alcaide, B.; Casarrubios, L.; Domhguez, G.; Sierra, M.A. Reaction of Chromium (Fischer) Carbenes and Sulfilimines. J. Org. Chem. 1993, 58, 3886–3894. [Google Scholar] [CrossRef]
  26. Sharma, A.K.; Ku, T.; Dawson, A.D.; Swern, D. Iminosulfuranes. XV. Dimethyl Sulfoxide-trifluoroacetic Anhydride. New and Efficient Reagent for the Preparation of Iminosulfuranes. J. Org. Chem. 1975, 40, 2758–2764. [Google Scholar] [CrossRef]
  27. Claus, P.K.; Rieder, W.; Hofbauer, P.; Vilsmaier, E. N-Aryl Sulfimides. Tetrahedron 1975, 31, 505–510. [Google Scholar] [CrossRef]
  28. Warthmann, W.; Schmidt, A. Reaktionsprodukte aus Chlorsulfonium-Salzen und Alkoholen bzw. Wasser und deren IR-Spektren. Chem. Ber. 1975, 108, 520–527. [Google Scholar] [CrossRef]
  29. Chasar, D.W.; Pratt, T.M.; Shockcor, J.P. The Reaction of Anhydrous HCl/Chloroform with Diaryl Sulfoxides. Phosphorus Sulfur Silicon Relat. Elem. 1980, 8, 183–186. [Google Scholar]
  30. Madesclaire, M. Reduction of Sulfoxides to Thioethers. Tetrahedron 1988, 44, 6537–6580. [Google Scholar] [CrossRef]
  31. Claus, P.; Vycudilik, W. Methylthiomethylierung von Aromatischen Aminen: N-Aryl-S,S-dimethylsulfimide als Zwischenstufen. Tetrahedron Lett. 1968, 9, 3607–3610. [Google Scholar] [CrossRef]
  • Sample Availability: Samples of the compounds are available from the corresponding author.
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top