The reaction of 4,5-Dichloro-1,2,3-dithiazolium chloride with sulfimides: A new synthesis of N-Aryl-1,2,3-dithiazolimines

Article abstract of DOI:10.3390/molecules14072356

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

Full text of DOI:10.3390/molecules14072356

Molecules 2009, 14, 2356-2362; doi:10.3390/molecules14072356
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
The Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride with
Sulfimides: A New Synthesis of N-Aryl-1,2,3-dithiazolimines
Andreas S. Kalogirou and Panayiotis A. Koutentis *
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus;
E-mail: andreas_ch05@hotmail.com (A-S.K.)
* Author to whom correspondence should be addressed; E-mail: koutenti@ucy.ac.cy;
Tel.: +35722892783; Fax: +35722892809
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 [2-4], antifungal [5-
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)
[9,17-19] 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

Molecules 2009, 14
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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.
Cl
Cl
Ar
N
Cl
ArNH2
+ S
Cl _
N
S
N
S
S
1
2
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
o
ca. 20 C 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.
Cl
Cl
Cl
N
Ar
Method A or B
+ S
Cl_
N
N
S
S
S
1
8-10
Method Conditions (equiv.)
Yields (%)
A
B
A
B
A
B
4-NO2C6H4N=S(Me)2 3 (1), 2 h
i) 4-NO2C6H4NH2 (1), 2.5 h, ii) C5H5N (2), 2 h
PhN=S(Me)2 4 (1), 3 h
i) PhNH2 (1), 0.5 h, ii) C5H5N (2), 2 h
4-MeC6H4N=S(Me)2 5 (1), 2.5 h
i) 4-MeC6H4NH2 (1), 1 h, ii) C5H5N (2), 2 h
8 (84)
8 (85), (lit. [21], 85)
9 (94)
9 (92), (lit. [21], 92)
10 (87)
10 (93), (lit. [21], 95)

Molecules 2009, 14
2358
Repeating the reaction of the N-(4-nitrophenyl)sulfimide 3 with Appel salt 1 in dry MeCN at ca.
o
20 C 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.
Me
Me
+
Cl_
Cl
+S
Cl_
Cl
Me
+S
S
Ar
N
_
Me
N
Ar
Cl
N
Cl
S
S
N
1
S
Me
+S
Me
Ar
2 Cl_
N
Cl
Ar
N
Cl
_
+ S
N
_
Me2SCl+Cl
S
N
S
S
12
11
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.

Molecules 2009, 14
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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
1
ATR accessory and strong, medium and weak peaks are represented by s, m and w, respectively. H-
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
tolyl)sulfimide
3
[26], S,S-dimethyl-N-phenylsulfimide
4
[26], S,S-dimethyl-N-(4-
[27], and N-benzoyl-
5
[26], S,S-dimethyl-N-(pyrid-2-yl)sulfimide
6
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
o
DCM (10 ml) at ca. 20 C, 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-
o
1,2,3-dithiazol-5-ylidene)-4-nitrobenzenamine 8 (110.1 mg, 84%) as yellow needles, mp 161-162 C
(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,
o
0.48 mmol) gave the title compound 9 (103.1 mg, 94%) as yellow needles, mp 61-62 C (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
o
compound 9 (101.9 mg, 87%) as yellow needles, mp 64-65 oC (lit. [5], 66-67 C) (from cyclohexane)
identical with an authentic sample.

Molecules 2009, 14
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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
o
compound 9 (100.9 mg, 92%) as yellow needles, mp 61-62 oC (lit. [5], 63-65 C) (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.
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.
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.
4. Joseph, R.W.; Antes, D.L.; Osei-Gyimah, P. Antimicrobial Compounds with Quick Speed of Kill.
US Pat. 5688744, 1997.
5. Moore, J.E. Certain 4-Halo-5-aryl-1,2,3-dithiazole Compounds and their Preparation. US Pat.
4059590, 1977.
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, 1980.

Molecules 2009, 14
2361
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.
8. Mayer, R.; Foerster, E.; Matauschek, B. Verfahren zur Herstellung von Aromatisch oder
Heteroaromatisch Substituierten Cyanthioformamiden. DD Pat. 212387, 1984.
9. Konstantinova, L.S.; Rakitin, O.A. Synthesis and Properties of 1,2,3-Dithiazoles, Russ. Chem.
Rev. 2008, 77, 521-546.
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.
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.
12. Rees, C.W. Polysulfur-nitrogen Heterocyclic Chemistry. J. Heterocycl. Chem. 1992, 29, 639-651.
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.
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.
15. Christoforou, I.C.; Koutentis, P.A.; Michaelidou, S.S. 1,2,3-Dithiazole Chemistry in Heterocyclic
Synthesis. Arkivoc 2006, 7, 207-223.
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.
17. Rakitin, O.A. In 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.
18. Kim, K. Synthesis and Reactions of 1,2,3-Dithiazoles. J. Sulfur Chem. 1998, 21, 147-207.
19. Kim, K. Recent Advances in 1,2,3-Dithiazole Chemistry. Phosphorus Sulfur Silicon Relat. Elem.
1997, 120, 229-244.
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.
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.
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.
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.
25. Alcaide, B.; Casarrubios, L.; Domhguez, G.; Sierra, M.A. Reaction of Chromium (Fischer)
Carbenes and Sulfilimines. J. Org. Chem. 1993, 58, 3886-3894.
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.

Molecules 2009, 14
2362
27. Claus, P.K.; Rieder, W.; Hofbauer, P.; Vilsmaier, E. N-Aryl Sulfimides. Tetrahedron 1975, 31,
505-510.
28. Warthmann, W.; Schmidt, A. Reaktionsprodukte aus Chlorsulfonium-Salzen und Alkoholen bzw.
Wasser und deren IR-Spektren. Chem. Ber. 1975, 108, 520-527.
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.
30. Madesclaire, M. Reduction of Sulfoxides to Thioethers. Tetrahedron 1988, 44, 6537-6580.
31. Claus, P.; Vycudilik, W. Methylthiomethylierung von Aromatischen Aminen: N-Aryl-S,S-
dimethylsulfimide als Zwischenstufen. Tetrahedron Lett. 1968, 9, 3607-3610.
Sample Availability: Samples of the compounds are available from the corresponding author.
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