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Short Note

(Z)-2-{[(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino](methylthio)methylene}malononitrile

by
Andreas S. Kalogirou
1,* and
Panayiotis A. Koutentis
2
1
Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenis Str., Engomi, P.O. Box 22006, 1516 Nicosia, Cyprus
2
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
*
Author to whom correspondence should be addressed.
Molbank 2022, 2022(1), M1354; https://doi.org/10.3390/M1354
Submission received: 25 February 2022 / Revised: 9 March 2022 / Accepted: 11 March 2022 / Published: 13 March 2022
(This article belongs to the Section Organic Synthesis)
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Abstract

:
Reaction of 4,5-dichloro-1,2,3-dithiazolium chloride with 2-[amino(methylthio)methylene])malononitrile (1 equiv) in the presence of pyridine (2 equiv) gave (Z)-2-{[(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino](methylthio)methylene}malononitrile in 20% yield. The compound was fully characterized.

1. Introduction

Isothiazoles are isomers of thiazoles that find uses in the medicinal (e.g., antirhinoviral, enteroviral [1,2,3,4] and anticancer activity [5], and as cathepsin C inhibitors [6]) and agrochemical (e.g., as fungicides, insecticides and acaricides [7,8,9]) sciences. Isothiazoles also have industrial applications, e.g., as dyes [10] and corrosion inhibitors [11], while they are also useful synthetic intermediates (e.g., Woodward’s synthesis of colchicine [12]). The synthesis, chemistry and applications of isothiazoles have been extensively reviewed [13,14,15].
A group of important isothiazole scaffolds are isothiazole-carbonitriles [16,17,18,19,20,21,22,23,24]. For example, isothiazole-carbonitriles 1–3 (Scheme 1) are precursors for the preparation of insecticides [25], herbicides [9] and other potent biocides [26]. Recently, we developed the synthesis of isothiazole-carbonitriles 4 starting from (4-chloro-5H-1,2,3-dithiazolylidene)acetonitriles 5, using gaseous HCl or HBr (Scheme 1) [27].

2. Results and Discussion

Another interesting synthesis of isothiazoles 6 directly from Appel’s salt 7 and primary enamines was reported by Rees [28]. In this work, two examples were reported with medium to good yields, while the reaction was proposed to proceed via the dithiazole ylidenes 8 (Scheme 2). Inspired by this work, we decided to investigate the same reaction with the analogous 2-[amino(methylthio)methylene]malononitrile that after nucleophilic addition to Appel’s salt 7 and elimination of cyanogen chloride could give ylidene 9.
Nevertheless, the reaction of Appel’s salt 7 with 2-[amino(methylthio)methylene]malononitrile (1 equiv) in MeCN, for 1 h, followed by addition of pyridine (2 equiv) and further stirring for 24 h gave the yellow colored product (Z)-2-{[(4-chloro-5H-1,2,3-dithiazol-5-ylidene)amino](methylthio)methylene}malononitrile (10) in 20% yield together with traces of the usual Appel’s salt degradation products (Scheme 3). The desired isothiazole 6c was not observed, indicating that either the enaminic reagent preferentially reacts with Appel’s salt 7 via the nucleophilic nitrogen instead of the enamine carbon, and/or that isothiazole 6c did form but was reactive and could not be isolated.
Product 10 was isolated as yellow needles, mp 172–174 °C (from DCE/c-hexane). UV-vis spectroscopy supported an intact dithiazole ring (λmax 374 nm, log ε 2.99). FTIR spectroscopy showed two cyano ν(C≡N) stretches at 2224 and 2216 cm−1, while mass spectrometry revealed a molecular ion (MH +) peak of m/z 275 (100%) along with a MH++2 isotope peak at 277 (73%) that supported the presence of a single chlorine. 13C NMR spectroscopy showed the presence of one CH3 resonance and six quaternary carbon resonances (see Supplementary Materials for the complete spectra), while a correct elemental analysis (CHN) was obtained for the molecular formula C7H3ClN4S3. Tentatively, the imine geometry was assigned as Z owing to steric and electronic repulsion between the C-4 chloride and the sulfide group. Despite the low yield of its preparation, imine 10 is a multifunctional dithiazole and its chemistry will be investigated in the future. An example of the potential reactivity of this compound is the ring opening of the dithiazole by various thiophiles followed by ring closure on the cyano groups that could yield pyrimidines. Alternatively, Michael addition onto the acrylonitrile unit could then lead to cyclization on to the dithiazole C-4 position.

3. Materials and Methods

The reaction mixture was 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 melting point was determined using a PolyTherm-A, Wagner & Munz, Kofler - Hotstage Microscope apparatus (Wagner & Munz, Munich, Germany). The solvent used for recrystallization is indicated after the melting point. The UV-vis spectrum was obtained using a Perkin-Elmer Lambda-25 UV-vis spectrophotometer (Perkin-Elmer, Waltham, MA, USA) and inflections are identified by the abbreviation “inf”. The IR spectrum was recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer (Shimadzu, Kyoto, Japan) with Pike Miracle Ge ATR accessory (Pike Miracle, Madison, WI, USA) 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 500 instrument [at 500 and 125 MHz, respectively, (Bruker, Billerica, MA, USA)]. Deuterated solvents were used for homonuclear lock and the signals are referenced to the deuterated solvent peaks. Attached proton test (APT) NMR studies were used for the assignment of the 13C peaks as CH3, CH2, CH and Cq (quaternary). The Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) mass spectrum (+ve mode) was recorded on a Bruker Autoflex III Smartbeam instrument (Bruker). The elemental analysis was run by the London Metropolitan University Elemental Analysis Service. 4,5-Dichloro-1,2,3-dithiazolium chloride (7) [29] and 2-[amino(methylthio)methylene]malononitrile [30] were prepared according to the literature procedures.

(Z)-2-{[(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino](methylthio)methylene}malononitrile (10)

To a stirred suspension of 4,5-dichloro-1,2,3-dithiazolium chloride (7) (104.3 mg, 0.50 mmol) in DCM (2 mL) was added 2-[amino(methylthio)methylene]malononitrile (69.6 mg, 0.50 mmol) and the reaction mixture was stirred at ca. 20 °C for 1 h. Pyridine (81 μL, 1.00 mmol) was then added and the reaction mixture was stirred for another 24 h. The mixture was then adsorbed onto silica and chromatographed (n-hexane/DCM 20:80) to give the title compound 10 (27 mg, 20%) as yellow needles, mp 172–174 °C (from DCE/c-hexane); Rf 0.30 (n-hexane/DCM 20:80); (found: C, 30.73; H, 1.11; N, 20.33. C7H3ClN4S3 requires C, 30.60; H, 1.10; N, 20.39%); λmax(DCM)/nm 295 (log ε 3.12), 374 (2.99), 389 inf (2.93); vmax/cm−1 2933w (alkyl C–H), 2224m and 2216m (C≡N), 1572m, 1560m, 1557s, 1553s, 1528w, 1489m, 1470s, 1454w, 1416w, 1323w, 1252m, 1186m, 1123m, 988w, 935m, 924m, 901w, 870s, 839w, 810m, 716s; δH(500 MHz; CDCl3) 2.44 (3H, s, CH3); δC(125 MHz; CDCl3) 181.4 (Cq), 163.6 (Cq), 147.2 (Cq), 112.2 (Cq), 111.5 (Cq), 66.9 (Cq), 15.0 (CH3); m/z (MALDI-TOF) 277 (MH++2, 73%), 275 (MH+, 100), 239 (M+-Cl, 3), 229 (M+-SMe+2, 25), 227 (M+-SMe, 60), 204 (MH+-SMe-CN+2, 14), 202 (MH+-SMe-CN, 37), 74 (26).

Supplementary Materials

The following supporting information can be downloaded online, mol file, 1H and 13C NMR spectra.

Author Contributions

A.S.K. and P.A.K. conceived the experiments; A.S.K. performed the experiments; A.S.K. wrote the paper; A.S.K. and P.A.K. edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Cyprus Research Promotion Foundation, grant numbers ΣΤΡAΤHΙΙ/0308/06, NEKYP/0308/02 ΥΓΕΙA/0506/19 and ΕΝΙΣΧ/0308/83.

Acknowledgments

The authors thank the following organizations and companies in Cyprus for generous donations of chemicals and glassware: The State General Laboratory, the Agricultural Research Institute, the Ministry of Agriculture, MedoChemie Ltd., Medisell Ltd. and Biotronics Ltd. Furthermore, we thank the A. G. Leventis Foundation for helping to establish the NMR facility at the University of Cyprus.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Molbank 2022 m1354 sch001 550
Scheme 1. Structure of isothiazole-carbonitriles 1–3 and synthesis of isothiazoles 4 from (4-chloro-5H-1,2,3-dithiazolylidene)acetonitriles 5.
Scheme 1. Structure of isothiazole-carbonitriles 1–3 and synthesis of isothiazoles 4 from (4-chloro-5H-1,2,3-dithiazolylidene)acetonitriles 5.
Molbank 2022 m1354 sch001
Molbank 2022 m1354 sch002 550
Scheme 2. Synthesis of isothiazoles 6 from Appel’s salt 7 and structures of intermediate dithiazole ylidenes 8 and 9.
Scheme 2. Synthesis of isothiazoles 6 from Appel’s salt 7 and structures of intermediate dithiazole ylidenes 8 and 9.
Molbank 2022 m1354 sch002
Molbank 2022 m1354 sch003 550
Scheme 3. Reaction of Appel’s salt 7 with 2-[amino(methylthio)methylene]malononitrile.
Scheme 3. Reaction of Appel’s salt 7 with 2-[amino(methylthio)methylene]malononitrile.
Molbank 2022 m1354 sch003
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MDPI and ACS Style

Kalogirou, A.S.; Koutentis, P.A. (Z)-2-{[(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino](methylthio)methylene}malononitrile. Molbank 2022, 2022, M1354. https://doi.org/10.3390/M1354

AMA Style

Kalogirou AS, Koutentis PA. (Z)-2-{[(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino](methylthio)methylene}malononitrile. Molbank. 2022; 2022(1):M1354. https://doi.org/10.3390/M1354

Chicago/Turabian Style

Kalogirou, Andreas S., and Panayiotis A. Koutentis. 2022. "(Z)-2-{[(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)amino](methylthio)methylene}malononitrile" Molbank 2022, no. 1: M1354. https://doi.org/10.3390/M1354

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