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Article

The Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride with Sulfimides: A New Synthesis of N-Aryl-1,2,3-dithiazolimines

by
Andreas S. Kalogirou
and
Panayiotis A. Koutentis
*
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
*
Author to whom correspondence should be addressed.
Molecules 2009, 14(7), 2356-2362; https://doi.org/10.3390/molecules14072356
Submission received: 26 May 2009 / Revised: 10 June 2009 / Accepted: 12 June 2009 / Published: 2 July 2009
(This article belongs to the Special Issue Advances in Heterocyclic Chemistry)
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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.

Graphical Abstract

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.
Molecules 14 02356 g001 550
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
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).
Molecules 14 02356 g002 550
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.

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  • Sample Availability: Samples of the compounds are available from the corresponding author.

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MDPI and ACS Style

Kalogirou, A.S.; Koutentis, P.A. The Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride with Sulfimides: A New Synthesis of N-Aryl-1,2,3-dithiazolimines. Molecules 2009, 14, 2356-2362. https://doi.org/10.3390/molecules14072356

AMA Style

Kalogirou AS, Koutentis PA. The Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride with Sulfimides: A New Synthesis of N-Aryl-1,2,3-dithiazolimines. Molecules. 2009; 14(7):2356-2362. https://doi.org/10.3390/molecules14072356

Chicago/Turabian Style

Kalogirou, Andreas S., and Panayiotis A. Koutentis. 2009. "The Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride with Sulfimides: A New Synthesis of N-Aryl-1,2,3-dithiazolimines" Molecules 14, no. 7: 2356-2362. https://doi.org/10.3390/molecules14072356

APA Style

Kalogirou, A. S., & Koutentis, P. A. (2009). The Reaction of 4,5-Dichloro-1,2,3-dithiazolium Chloride with Sulfimides: A New Synthesis of N-Aryl-1,2,3-dithiazolimines. Molecules, 14(7), 2356-2362. https://doi.org/10.3390/molecules14072356

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