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Article

The Conversion of 5,5′-Bi(1,2,3-dithiazolylidenes) into Isothiazolo[5,4-d]isothiazoles

1
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991, Russia
2
Nanotechnology Education and Research Center, South Ural State University, Chelyabinsk 454080, Russia
3
Department of Chemistry, University of Cyprus, P.O. Box 20537, Nicosia 1678, Cyprus
4
Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenis Str., Engomi, P.O. Box 22006, Nicosia 1516, Cyprus
5
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 119991, Russia
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(6), 1257; https://doi.org/10.3390/molecules23061257
Received: 15 May 2018 / Revised: 21 May 2018 / Accepted: 24 May 2018 / Published: 24 May 2018
(This article belongs to the Special Issue Recent Advances in Nitrogen-Containing Aromatic Heterocycles)

Abstract

:
Thermolysis of 4,4′-dichloro-, 4,4′-diaryl-, and 4,4′-di(thien-2-yl)-5,5′-bi(1,2,3-dithiazol-ylidenes) affords the respective 3,6-dichloro-, 3,6-diaryl- and 3,6-di(thien-2-yl)isothiazolo[5,4-d]-isothiazoles in low to high yields. The transformation of the 4,4′-diaryl- and 4,4′-di(thien-2-yl)-5,5′-bi(1,2,3-dithiazolylidenes) occurs at lower temperatures in the presence of the thiophiles triphenylphosphine or tetraethylammonium iodide. Optimized reaction conditions and a mechanistic rationale for the thiophile-mediated ring transformation are presented.

Graphical Abstract

1. Introduction

Thienothiophenes are rigid π rich arenes used to build biologically active compounds [1] and semi-conducting or fluorescent small molecules, oligomers and polymers [2,3]. Owing to their high HOMO energy levels, thienothiophenes are oxidatively unstable but this can be overcome by introducing electron withdrawing substituents, or by replacing a ring sp2 carbon with a more electronegative sp2 nitrogen. An example of the latter strategy is the replacement of thienothiophene with thiazolo[5,4-d]thiazole (1). Since the first thiazolo[5,4-d]thiazole (1) was reported in 1960 [4], over 400 analogues have been made and many were incorporated into dyes, oligomers and polymers for semiconductors and plastic electronics [5,6]. Interestingly, the isomeric thiazolo[4,5-d]thiazole (2) which, like thiazolo[5,4-d]thiazole (1), shares a common C-C bond between the two thiazoles is less well known; only 14 analogues are known [7,8,9,10,11,12,13]. Despite this, several analogues have useful properties as plant fungacides [10], antitumour agents [7], and as non-linear optical materials [8]. The isomeric isothiazole analogues are also poorly studied, which is surprising as they offer the possibility of fusion across more than one common C-C bond, affording up to six possible isothiazoloisothiazole biheterole structures. Of these, syntheses and chemistry of only two have been reported: isothiazolo[5,4-d]isothiazole (3) [14,15,16] and isothiazolo[4,5-d]-isothiazole (4) [17,18,19] (Figure 1).
Three strategies are reported for the preparation of isothiazolo[5,4-d]isothiazoles: (1) 3,6-bis(acylimino)-3H,6H-[1,2]dithiolo[4,3-c][1,2]dithioles 5 react with hydroxylamine to undergo an Assisted Nucleophilic Ring Opening Ring Closure (ANRORC) style exchange of S for NH to give 3,6-bis(acylamino)isothiazolo[5,4-d]isothiazoles 6 [15]; (2) 1,4-diphenylbuta-1,3-diene (7) reacts with trithiazyl trichloride to afford 3,6-diphenylisothiazolo[5,4-d]isothiazole (8b) [14]; and (3) 5-benzoyl-3-phenylisothiazole oxime (9) reacts with disulfur dichloride in DMF at 100 °C for 16 h to give isothiazolo[5,4-d]isothiazole (8b) [14,16] (Scheme 1). Considering this and the potential uses of isothiazolo[5,4-d]isothiazoles like 3 in the materials sciences, we were interested in developing a new complementary route to this ring system.
Recently, Rakitin et al. described the Cu(0)-mediated coupling of 4-substituted 5-chloro-1,2,3-dithiazolium chlorides 10 [20,21,22] to give (E)-4,4′-disubstituted 5,5′-bi(1,2,3-dithiazolylidenes) 11 [23]. Products 11 are similar to (E)-3,3′-bi(1,2-dithiolylidenes) 12 that undergo both thermal and light-mediated ring transformations to afford thieno[3,2-b]thiophenes 13 [24] (Scheme 2).
The chemistry of 1,2,3-dithiazoles has been extensively reviewed [25,26,27] and 4-chloro-5H-1,2,3-dithiazoles undergo both thermal [28,29,30,31] and ANRORC-mediated [32,33,34] ring transformations to afford various heterocycles, including both thiazoles [28,29,30,31,35,36,37,38] and isothiazoles [36,39,40,41,42]. As such, we proposed that 5,5′-bi(1,2,3-dithiazolylidenes) 11 could be similarly converted into isothiazolo[5,4-d]isothiazoles 8 providing a new route to this rare biheterole.

2. Results and Discussion

Early studies on (E)-4,4′-dichloro-5,5′-bi(1,2,3-dithiazolylidene) (11a) revealed the compound to be unstable. DCM solutions of dithiazolylidene 11a in the presence of daylight slowly became complex (by TLC). Furthermore, samples of crystalline dithiazolylidene 11a after several months also showed signs of decomposition. Chromatographic analysis of a decomposed sample revealed the presence of elemental sulfur (S8), 4-chloro-5H-1,2,3-dithiazole-5-thione (14) [43], 3,4-dichloro-isothiazole-5-carbonitrile (15) [39,44], a new compound identified as 3,6-dichloroisothiazolo- [5,4-d]isothiazole (8a) as well as several unstable (2D TLC), unidentified yellow and orange products (Scheme 3).
To the best of our knowledge, 3,6-dichloroisothiazolo[5,4-d]isothiazole (8a) is a new dihaloisothiazoloisothiazole and a potentially useful biheterole building block. To support its structure, single crystal XRD crystallography was carried out (Figure 2).
Interestingly, thermolysis of a neat sample of freshly prepared (E)-4,4′-dichloro-5,5′-bi(1,2,3-dithiazolylidene) (11a) (0.10 mmol) at ca. 300 °C under argon atmosphere led to the formation of the dichloroisothiazoloisothiazole 8a in a low yield (8%) together with elemental sulfur (S8) (TLC) (Table 1, entry 1). Fortunately, thermolysis of 4,4′-di(het)aryl-substituted bi(dithiazolylidenes) 11bf provided the corresponding 3,6-di(het)arylisothiazolo[5,4-d]isothiazoles 8bf in 82–96% yields (Table 1, entries 2–6).
Unable to scale up the thermolysis for the conversion of (E)-4,4′-dichloro-5,5′-bi(1,2,3-dithiazolylidene) 11a into the isothiazolo[5,4-d]isothiazole 8a we then investigated the use of thiophilic agents triphenylphosphine, BnEt3NCl or Et4NI, but obtained in each case only an intractable tarry mass. Not surprisingly, dichloroisothiazoloisothiazole 8a, which hosts a variety of highly electrophilic sites (S, Cl, C3/6 as well as C3a/6a) was unstable to the thiophiles. This was partially attributed to the excellent nucleofuge ability of the C3/6 chlorine substituents. This lability was also evident during efforts to carry out substitution of the chlorides by methoxide or pyrrolidine nucleophiles, the former leading to intractable baseline and the latter to a mixture of monocyclic oligosulfides (TLC, NMR) that could not be isolated pure. Moreover our efforts to carry out Suzuki-Miyaura [PhB(OH)2 (3 equiv), KF (3.5 equiv), 18-crown-6 (0.5 equiv), Pd(OAc)2 (10 mol %), PhMe, 110 °C], Stille [PhSnBu3 (3 equiv), Pd(Oac)2 (10 mol %), DMF, 100 °C or Pd Superstable (10 mol %), PhMe, 110 °C] or Sonogashira couplings [phenylacetylene (2.2 equiv), Et3N (4 equiv), PdCl2(Ph3P)2 (5 mol %), MeCN, 100 °C] led to only traces of product and mainly gave degradation of the ring system. The difficulty in displacing isothiazole C3 chlorides has been previously reported [45,46,47]. Analysis of the reaction mixtures (TLC) revealed S8 (TLC) supporting ring cleavage, presumably owing to a thiophilic attack.
In light of the above, and with the aim to develop a milder route to 3,6-di(het)aryl-isothiazolo[5,4-d]isothiazoles 11 we developed and optimized a thiophile-mediated ring transformation for (E)-4,4′-diphenyl-5,5′-bi(1,2,3-dithiazolylidene) (11b), which has no nucleofuges at either C4/4′ and gives a product with no nucleofuges at either C3/6 and therefore was more resistant to thiophile-mediated ring opening reactions (Table 2, entries 1–10). Interestingly, single crystal X-ray studies were also obtained to support both the (E)-geometry of the diphenyl- bi(dithiazolylidene) 11b and the structure of the final diphenyl-substituted isothiazoloisothiazole 8b (Figure 3). While both isothiazoloisothiazoles 8a and 8b have planar isothiazoloisothiazole core structures, the phenyl groups in the latter deviate in a conrotatory manner from the isothiazoloisothiazole plane by 8.7°.
Heating a toluene solution of the diphenylbi(dithiazolylidene) 11b at ca. 110 °C for 29 h led to its conversion into diphenylisothiazoloisothiazole 8b in 76% yield together with traces of S8 and 4-phenyl-5H-1,2,3-dithiazole-5-thione (14b) [20] (by TLC) (Table 2, entry 1). In the presence of thiophiles Et4NI or Ph3P the reaction proceeded significantly faster and in higher yield (Table 2, entries 2–10). When Ph3P (2–4 equiv) was used as thiophile, diphenylisothiazoloisothiazole 8b was formed in quantitative yield but was accompanied, as expected, by the formation of triphenylphosphine sulfide (Ph3P = S) in 75–78% yield (Table 2, entries 2 and 3), which required chromatographic separation. Fortunately, the use of Et4NI as thiophile worked equally well, and on a 0.5 mmol scale, in 5 mL of PhMe, the use of Et4NI (0.2 equiv) gave the fastest reaction (2 h) and a quantitative yield of product (Table 2, entry 5) which could be isolated without the need for chromatography. More or less equivalents of Et4NI led to longer reaction times (Table 2, entries 4 and 6). With these conditions in hand, we then investigated the effect of concentration and temperature. Fortunately, small variations in concentration did not affect the reaction times or yields (data not shown), and carrying out the reaction using 0.1 mmol of ylidene 11b in only 5 mL of PhMe continued to give a near quantitative yield of isothiazoloisothiazole 8b (95%) together with some dithiazolethione 14b (5%) (Table 2, entry 9), but at 0.2 mmol the yield of the desired product 8b dropped significantly (63%) and the amount of undesired dithiazolethione 14b increased (26%) (Table 2, entry 10). Lowering the reaction temperature with the use of PhH (bp 80 °C) instead of PhMe (bp 110 °C) led to no reaction after 10 h of heating (Table 2, entry 7) while the use of PhCl (bp 132 °C) led to a longer reaction time (8 h), lower yield (72%) and the formation of more dithiazolethione 14b (15%) compared to the PhMe (Table 2, entry 8). With the thiophile-mediated reaction of the diphenylbi(dithiazolylidene) 11b partially optimized we then carried out a minor investigation into the reactions scope (Table 2, entries 11–13).
Under the optimized reaction conditions, ylidenes bearing aryls containing electron withdrawing para-fluoro and electron releasing para-methoxy substitution worked to give the desired isothiazoloisothiazoles in moderate to excellent yields 69 and 99%, respectively (Table 2, entries 11 and 12). Furthermore, the important thien-2-yl group, an electron rich hetaryl that is important in organic electronic materials, was tolerated to afford 3,6-di(thien-2-yl)-isothiazolo[5,4-d]isothiazole (8e) in 92% yield (Table 2, entry 13), potentially opening up this biheterole system for study as a new π spacer for small organic molecules, oligomers or polymers in material sciences.
Interestingly, treating di(thien-2-yl)isothiazoloisothiazole 8e with N-bromosuccinimide (NBS) (2 equiv) in a mix of chloroform/acetic acid (50:50) heated at ca. 70 °C for 5 h afforded the useful 3,6-di(5,5′-dibromothien-2-yl)isothiazolo[5,4-d]isothiazole (16) in 63% yield (Scheme 4). Efforts to incorporate this moiety in oligomers and polymers for organic electronic applications are now in progress.

Mechanistic Rationale

Tentatively, we propose the thiophile-mediated reaction (Table 2) proceeded via an ANRORC style reaction pathway [32,33,34], where the thiophile attacks either the dithiazole S1 or S2 sulfurs to generate a ring opened species that then collapses to give the isothiazole ring system (Scheme 5). At this stage, it is not possible to give an accurate mechanism, as several possibilities exist. Previous studies, nevertheless, reveal the dithiazole S2 atom to be marginally more susceptible to thiophilic attack [49], and based on this we propose the ring opening of both dithiazoles to generate the dianion 17 that then collapses to the 14π 4,8-disubstituted [1–3]dithiazino[6,5-e][1,2,3]dithiazine 18 which collapses to the thermodynamically more stable 10π 3,6-disubstituted isothiazolo-[5,4-d]isothiazole 8 (Scheme 5). Attempts to treat 3,6-diphenylisothiazolo[5,4-d]isothiazole 8b with elemental sulfur or active sulfur (DABCO/S8) [50] led to no reaction supporting that the reaction was not in equilibrium and the product was not convertible back to the starting dithiazole 11b.
Similar ANRORC-style transformations of bis(1,2,3-dithiazoles) have been reported that afford difficult to access 1,3,4-thiadiazoles and thiazoles [37]. These transformations involved thiophile-mediated ring opening of one dithiazole to release a nucleophilic sulfur that was then intramolecularly trapped by the neighboring dithiazole to generate a new more thermodynamically stable heteroarene. More recently, evidence for the conversion of 1,2,3-dithiazoles into structurally related 1,2,4-dithiazines has also been reported [51].
The mechanistic rationale for the thermolysis of neat samples or for the decomposition of samples on prolonged storage or in solution, remains unclear and, similar to the ring transformation of (E)-3,3′-bi(1,2-dithiolylidene) to thieno[3,2-b]thiophenes could also involve homolytic pathways [24]. In the presence of spin trap agents such as 1,4-benzoquinone or (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl oxidanyl (TEMPO) we noted that the ring transformation was significantly slower.

3. Materials and Methods

3.1. General Methods and Materials

Powdered anhydrous Na2SO4 was used for drying organic extracts and all volatiles were removed under reduced pressure. Toluene was distilled over CaH2 before use. 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. Elemental analyses were performed on a 2400 Elemental Analyzer (Perkin Elmer Inc., Waltham, MA, USA). Melting points were determined on a Kofler hot-stage apparatus and are uncorrected. Solvents used for recrystallization are indicated after the melting point. 1H and 13C-NMR spectra were taken with a Bruker AM-300 (at 300.1 and 75.5 MHz) or Bruker DRX500 (at 500.1 and 125.8 MHz) or Bruker AV600 instrument (at 600.1 and 150.9 MHz) (Bruker Ltd., Moscow, Russia) with TMS as the standard. J values are given in Hz. MS spectra (EI, 70 eV) were obtained with a MAT INCOS 50 instrument (Thermo Finnigan LLC, San Jose, CA, USA). High-resolution MS spectra were measured on a Bruker MICROTOF II instrument using electrospray ionization (ESI). The measurement was operated in a positive ion mode (interface capillary voltage—4500 V) or in a negative ion mode (3200 V); mass range was from m/z 50 to 3000 Da; external or internal calibration was done with Electrospray Calibrant Solution (Fluka Chemicals Ltd., Gillingham, UK). A syringe injection was used for solutions in acetonitrile, methanol, or water (flow rate 3 μL/min). Nitrogen was applied as a dry gas; interface temperature was set at 180 °C. IR spectra were measured with a M-80 instrument (Carl Zeiss Jena GmbH, Jena, Germany) in KBr pellets. 4,4′-Disubstituted 5,5′-bi(1,2,3-dithiazolylidenes) 11ae [23] and (E)-1-(4-bromophenyl)-ethan-1-one oxime [52] were prepared according to the literature.
Data collection for a single crystals 8a, 8b, 8d and 11b (Figures S1–S4, Supporting Information, SI) was performed at the Center for Molecular Composition Studies of INEOS RAS on a Bruker Smart Apex II CCD diffractometer (Mo Kα radiation, λ = 0.71073 Å, graphite monochromator). Frames were integrated using the Bruker SAINT software package [53] using a narrow-frame algorithm, and a semiempirical absorption correction was applied with the SADABS program [54] using intensity data of the equivalent reflections. All the structures were solved by direct method and refined by the least-squares in anisotropic full-matrix approximation on F2hkl. The hydrogen atoms were calculated geometrically and refined in isotropic approximation using the riding model with the SHELX software package [55]. The refinement of the molecules with minor occupancy was performed with the restraints on anisotropic displacement parameters (EADP) and bond lengths and angles (SAME). Detailed crystallographic information is provided in Table 3 and as Supporting Information in CIF format that can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax: 44-1223-336033 using the reference CCDC numbers (Table 3).

3.2. (E)-4,4′-Bis(4-bromophenyl)-5,5′-Bi(1,2,3-dithiazolylidene) (11f)

To a stirred solution of (E)-1-(4-bromophenyl)ethan-1-one oxime [24] (428 mg, 2 mmol) and sulfur monochloride (0.64 mL, 4 mmol) in acetonitrile (15 mL) at ca. −5 °C under an argon atmosphere was added dropwise pyridine (0.96 mL, 6 mmol). The mixture was stirred at ca. −5 °C for 15 min, then copper powder (192 mg, 3 mmol) was added, the mixture was stirred at room temperature for 1.5 h and then poured into ice water (100 mL). The precipitate was filtered, washed with water, dried and extracted with CH2Cl2 (3 × 15 mL). The combined extracts were dried (CaCl2) and solvents were evaporated under reduced pressure. The residue was rapidly separated by flash chromatography (silica gel Merck 60, n-hexane and then n-hexane/CH2Cl2 mixtures) to afford the title compound 11f (346 mg, 67%) as a black powder, m.p. 181–182 °C (n-hexane); δH (300 MHz; СD2Cl2) 7.37 (d, 4H, J 6.6, Ar H), 7.67 (d, 4H, J 8.1, Ar H); δC (75 MHz; СD2Cl2) 157.1, 150.6, 132.7, 130.8, 127.6, 110.1; νmax (KBr) 3088, 3067, 3043, 1671, 1482, 1459, 1392, 1322, 1262, 1100, 1072, 1025, 1010, 827, 804, 758, 677 cm−1; m/z (EI) 518 (M+ + 4, 53%), 516 (M+ + 2, 100), 514 (M+, 46), 484 (24), 452 (68), 292 (3), 258 (3), 102 (9), 88 (10); HRMS m/z (ESI) 515.7903 [M]+ (calc. for C16H8Br2N2S4, m/z 515.7910).

3.3. General Thermolysis Procedure (Method 1)

4,4′-Disubstituted 5,5′-bi(1,2,3-dithiazolylidene) 11 (0.10 mmol) under an argon atmosphere was immersed into a preheated (~230–300 °C) Wood′s metal bath for 0.5 min. On cooling to ca. 20 °C the residue was triturated with n-hexane, filtered and recrystallized to give isothiazolo[5,4-d]-isothiazole 8 as colorless crystals (see Table 1).

3.4. General ANRORC Procedure (Method 2)

To a stirred solution of 4,4′-disubstituted 5,5′-bi(1,2,3-dithiazolylidene) 8 (0.05 mmol) in anhydrous toluene (5 mL) at ca. 20 °C was added Et4NI (0.2 equiv). The reaction mixture was then heated at reflux (ca. 110 °C) until complete consumption of the starting dithiazole 8 (by TLC). The reaction mixture was allowed to cool to ca. 20 °C, the volatiles removed in vacuo, and then the residue was triturated with n-hexane (1.5 mL), the precipitate was filtered and washed (acetone 2 × 1.5 mL) and dried. Recrystallisation of the residue gave the isothiazolo[5,4-d]isothiazole 8 as colorless crystals (see Table 2).

3.5. Data on Compounds 8af

3.5.1. 3,6-Dichloroisothiazolo[5,4-d]isothiazole (8a)

(Method 1: 2 mg, 8%) as colorless prisms, m.p. 210–212 °C (decomp.) (acetone). (Found: C, 22.98, N, 13.01. C4Cl2N2S2 requires C, 22.76; N, 13.27%); δC (300 MHz; CDCl3) 155.9, 138.4; νmax (KBr) 1596, 1332, 1188, 1076, 792, 768 cm−1; λmax (CH2Cl2)/nm 236 (log ε 3.31), 304 (3.98); m/z (EI) 214 (M+ + 4, 15%), 212 (M+ + 2, 63), 210 (M+, 95), 175 (11), 114 (22), 88 (50), 70 (100).

3.5.2. 3,6-Diphenylisothiazolo[5,4-d]isothiazole (8b)

(Method 1: 28.0 mg, 96%; Method 2: 14.6 mg, 99%) as colorless blocks, m.p. 203–204 °C (lit. [14], m.p. 200–202 °C) (acetone); (found: C, 65.43; H, 3.56; N, 9.25. C16H10N2S2 requires: C, 65.28; H, 3.42; N, 9.52%); δH (300 MHz; CDCl3) 8.00 (d, 4H, J 7.0, Ar H), 7.59–7.48 (m, 6H, Ar H); δC (75 MHz; CDCl3) 156.3, 156.1, 132.9, 130.2, 129.3, 127.3; νmax (KBr) 1620, 1420, 1330, 1280, 1160, 978, 802, 763, 692 cm−1; λmax (CH2Cl2)/nm 242 (log ε 4.59), 332 (4.32); m/z (EI) 294 (M+, 100%), 191 (77), 146 (37), 88 (100); HRMS m/z (ESI) 295.0336 [M + Na]+ (calc. for C16H10NaN2S2, m/z 295.0334).

3.5.3. 3,6-Bis(4-fluorophenyl)isothiazolo[5,4-d]isothiazole (8c)

(Method 1: 27.4 mg, 83%; Method 2: 11.4 mg, 69%), as colorless crystals, m.p. 268–269 °C (acetone); (found: C, 58.33; H, 2.62; N, 8.23. C16H8F2N2S2 requires: C, 58.17; H, 2.44; N, 8.48%); δH (300 MHz; DMSO-d6) 8.06 (dd, 4H, J 4.8, Ar H), 7.49 (t, 4H, J 8.4, Ar H); δC (150 MHz; DMSO-d6) 165.4 (d, 1JCF 226.5), 157.2, 155.9, 130.7 (d, 3JCF 7.2), 130.1, 117.9 (d, 2JCF 21.5); νmax (KBr) 1600, 1515, 1440, 1420, 1315, 1238, 1180, 1100, 980, 840, 805, 720 cm−1; λmax (CH2Cl2)/nm 242 (log ε 4.05), 330 (3.76); m/z (EI) 330 (M+, 50%), 235 (8), 209 (32), 164 (30), 121 (35), 88 (100); HRMS m/z (ESI) 330.0091 [M]+ (calc. for C16H8F2N2S2, m/z 330.0098).

3.5.4. 3,6-Bis(4-methoxyphenyl)isothiazolo[5,4-d]isothiazole (8d)

(Method 1: 30.0 mg, 85%; Method 2: 17.6 mg, 99%), as colorless prisms, m.p. 238–239 °C (acetone); (found: C, 61.13; H, 4.15; N, 7.71. C16H14N2O2S2 requires: C, 60.99; H, 3.98; N, 7.90%); δH (300 MHz; DMSO-d6) 7.92 (d, 4H, J 8.1, Ar H), 7.22 (d, 4H, J 8.8, Ar H), 3.89 (s, 6H, OCH3); δC (150 MHz; DMSO-d6) 162.4, 157.7, 156.7, 129.8, 126.4, 116.3, 56.8 (OMe); νmax (KBr) 1608, 1576, 1532, 1416, 1312, 1296, 1268, 1176, 1024, 832, 800 cm−1; λmax (CH2Cl2)/nm 249 (log ε 4.35), 344 (4.17); m/z (EI) 354 (M+, 45%), 311 (2), 221 (22), 177 (27), 134 (30), 88 (100); HRMS m/z (ESI) 355.0546 [M + H]+ (calc. for C18H15N2O2S2, m/z 355.0546).

3.5.5. 3,6-Di(thien-2-yl)isothiazolo[5,4-d]isothiazole (8e)

(Method 1: 28.0 mg, 90%; Method 2: 14.1 mg, 92%), as colorless crystals, m.p. 250–251 °C (acetone); (found: C, 47.26; H, 2.13; N, 8.93. C12H6N2S4 requires: C, 47.03; H, 1.97; N, 9.14%); δH (300 MHz; CDCl3) 7.52–7.48 (m, 4H, thienyl H), 7.21–7.18 (m, 2H, thienyl H); δC (75 MHz; CDCl3) 155.3, 150.9, 136.7, 129.0, 128.2, 127.7; νmax (KBr) 3095 and 3031 (aryl С-H), 1652, 1536, 1448, 1424, 1344, 1256, 1224, 1048, 852, 800, 760, 704, 680, 664, 624 cm−1; λmax (CH2Cl2)/nm 257 (log ε 4.08), 348 (3.98); m/z (EI) 306 (M+, 87%), 223 (3), 197 (20), 165 (9), 153 (20), 109 (25), 88 (100); HRMS m/z (ESI) 306.9463 [M + H]+ (calc. for C12H7N2S4, m/z 306.9463).

3.5.6. 3,6-Bis(4-bromophenyl)isothiazolo[5,4-d]isothiazole (8f)

(Method 1: 30.0 mg, 82%), as colorless crystals, m.p. 234–235 °C (acetone); (found: C, 42.35; H, 1.59; N, 6.45. C16H8Br2N2S2 requires: C, 42.50; H, 1.78; N, 6.20%); δH (300 MHz; СD2Cl2) 7.93 (d, 4H, J 9.0, Ar H), 7.76 (d, 4H, J 9.0, Ar H); δC (125 MHz; СD2Cl2) 157.5, 154.7, 132.6, 131.7, 128.9, 122.7; νmax (KBr) 1588, 1429, 1401, 1322, 1289, 1184, 1075, 1008, 972, 830, 805, 710, 652 cm−1; λmax (CH2Cl2)/nm 254 (log ε 4.77), 337 (4.44); m/z (EI) 454 (M+ + 4, 57%), 452 (M+ + 2, 100), 450 (M+, 51), 295 (5), 271 (17), 190 (43), 155 (17), 102 (32), 88 (75); HRMS m/z (ESI) 452.8541 [M + H]+ (calc. for C16H9Br2N2S2, m/z 452.8548).

3.6. Bromination of 3,6-Di(thien-2-yl)isothiazolo[5,4-d]isothiazole (16)

3,6-Di(5,5′-dibromothien-2-yl)isothiazolo[5,4-d]isothiazole (16)

To a stirred solution of 3,6-di(thien-2-yl)isothiazolo[5,4-d]isothiazole (8f) (73.4 mg, 0.24 mmol) in CHCl3/AcOH (50:50) (12 mL) at ca. 20 °C was added NBS (85.0 mg, 0.48 mmol). The mixture was then heated to ca. 70 °C for 7 h then allowed to cool to ca. 20 °C. The precipitate was filtered, washed with diethyl ether (2 × 2 mL), dried to afford the title compound 16 (34 mg, 31%) as colorless crystals. The combined solvents were evaporated under reduced pressure and separated by column chromatography on silica gel to afford addition quantity of the title compound 16 (36 mg, 32%). Combined yield of 3,6-di(5,5′-dibromothien-2-yl)isothiazolo[5,4-d]isothiazole (16) (70.0 mg, 63%); m.p. 255–257 °C (acetone); (found: C, 31.28; H, 1.03; N, 6.25. C12H4Br2N2S4 requires: C, 31.05; H, 0.87; N, 6.03%); δH(300 MHz; D2SO4) 6.25 (d, 2H, J 4.4, thienyl H), 6.06 (d, 2H, J 4.4, thienyl H); δC (125 MHz; D2SO4) 150.0, 141.9, 137.2, 133.8, 131.1, 125.6; νmax (KBr) 3091, 3051, 1656, 1598, 1543, 1452, 1398, 1349, 1299, 1212, 1120, 976, 934, 805, 782, 723, 660 cm−1; λmax (CH2Cl2)/nm 279 (log ε 4.32), 354 (4.32); m/z (EI) 466 (M+ + 4, 60%), 464 (M+ + 2, 100), 462 (M+, 46), 384 (63), 306 (12), 222 (6), 88 (25); HRMS m/z (ESI) 464.7670 (MH)+ (calc. for C12H5Br2N2S4, m/z 464.7675).

4. Conclusions

4,4′-Dichloro- and 4,4′-di(het)aryl-5,5′-bi(1,2,3-dithiazolylidenes) undergo thermolysis to afford the respective 3,6-dichloro- and 3,6-di(het)arylisothiazolo[5,4-d]isothiazoles in low to high yields. The transformation of the di(het)arylbi(dithiazolylidenes) into di(het)arylisothiazoloisothiazoles can be achieved under milder conditions via thiophile-mediated ANRORC-type reactions with the use of Et4NI (0.2 equiv) as thiophile. The transformation provides access to 3,6-di(thien-2-yl)-substituted isothiazolo[5,4-d]isothiazole which can be valued scaffolds in molecular electronic materials.

Supplementary Materials

Figures S1–S19. Crystallographic (cif files for compounds 8a (CCDC 1840070), 8b (CCDC 1840071), 8d (CCDC 1840073) and 11b (CCDC 1840072) and characterization data including 1H and 13C-NMR spectra for compounds 8af, 11f and 16.

Author Contributions

O.A.R. and P.A.K. conceived and designed the study; L.S.K., I.V.B., V.V.S., V.V.P. and A.S.K. performed the experiments; L.S.K., I.V.B., V.V.S. analyzed the data; K.A.L. carried out the XRD studies; all authors contributed to writing and editing the paper.

Funding

This research was funded by Russian Science Foundation grant number 15-13-10022.

Acknowledgments

The authors thank the Russian Science Foundation, the Cyprus Research Promotion Foundation and 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. V.V.P. is grateful to South Ural State University.

Conflicts of Interest

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

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Sample Availability: Samples of the compounds are available from the authors.
Figure 1. Known [1,2] and [1,3] thiazolothiazole ring systems 14.
Figure 1. Known [1,2] and [1,3] thiazolothiazole ring systems 14.
Molecules 23 01257 g001
Scheme 1. Known routes to isothiazolo[5,4-d]isothiazoles.
Scheme 1. Known routes to isothiazolo[5,4-d]isothiazoles.
Molecules 23 01257 sch001
Scheme 2. Ring transformation of (E)-3,3′-bi(1,2-dithiolylidenes) 12 into thieno[3,2-b]thiophenes 13 and the analogous proposed transformation of 5,5′-bi(1,2,3-dithiazolylidenes) 11 into isothiazolo[5,4-d]isothiazoles 8.
Scheme 2. Ring transformation of (E)-3,3′-bi(1,2-dithiolylidenes) 12 into thieno[3,2-b]thiophenes 13 and the analogous proposed transformation of 5,5′-bi(1,2,3-dithiazolylidenes) 11 into isothiazolo[5,4-d]isothiazoles 8.
Molecules 23 01257 sch002
Scheme 3. Decomposition of (E)-4,4′-dichloro-5,5′-bi(1,2,3-dithiazolylidene) (11a).
Scheme 3. Decomposition of (E)-4,4′-dichloro-5,5′-bi(1,2,3-dithiazolylidene) (11a).
Molecules 23 01257 sch003
Figure 2. X-ray structure of 3,6-dichloroisothiazolo[5,4-d]isothiazole (8a). (CCDC 1840070). Thermal ellipsoids are at 50% probability.
Figure 2. X-ray structure of 3,6-dichloroisothiazolo[5,4-d]isothiazole (8a). (CCDC 1840070). Thermal ellipsoids are at 50% probability.
Molecules 23 01257 g002
Figure 3. X-ray structures of (E)-4,4′-diphenyl-5,5′-bi(1,2,3-dithiazolylidene) (11b) (CCDC 1840072) (top) and 3,6-diphenylisothiazolo[5,4-d]isothiazole (8b) (CCDC 1840071) (bottom). Thermal ellipsoids are at 50% probability and hydrogens are omitted for clarity.
Figure 3. X-ray structures of (E)-4,4′-diphenyl-5,5′-bi(1,2,3-dithiazolylidene) (11b) (CCDC 1840072) (top) and 3,6-diphenylisothiazolo[5,4-d]isothiazole (8b) (CCDC 1840071) (bottom). Thermal ellipsoids are at 50% probability and hydrogens are omitted for clarity.
Molecules 23 01257 g003aMolecules 23 01257 g003b
Scheme 4. Preparation of 3,6-di(5,5′-dibromothien-2-yl)isothiazolo[5,4-d]isothiazole (16).
Scheme 4. Preparation of 3,6-di(5,5′-dibromothien-2-yl)isothiazolo[5,4-d]isothiazole (16).
Molecules 23 01257 sch004
Scheme 5. Tentative mechanism for the Et4NI-mediated ring transformation of dithiazolylidenes 11 into isothiazolo[5,4-d]isothiazoles 8.
Scheme 5. Tentative mechanism for the Et4NI-mediated ring transformation of dithiazolylidenes 11 into isothiazolo[5,4-d]isothiazoles 8.
Molecules 23 01257 sch005
Table 1. Thermolysis of neat 4,4′-disubstitued 5,5′-bi(1,2,3-dithiazolylidenes) 11af (0.10 mmol) for 2 min under argon to give 3,6-disubstituted isothiazolo[5,4-d]isothiazoles 8af.
Table 1. Thermolysis of neat 4,4′-disubstitued 5,5′-bi(1,2,3-dithiazolylidenes) 11af (0.10 mmol) for 2 min under argon to give 3,6-disubstituted isothiazolo[5,4-d]isothiazoles 8af.
EntryRTemp (°C)Yield 8 (%)
1Cl3008a (8)
2Ph2308b (96)
34-FC6H42508c (83)
44-MeOC6H42808d (85)
5thien-2-yl2508e (90)
64-BrC6H42708f (82)
Table 2. Optimization of the ring transformation of (E)-4,4′-diphenyl-5,5′-bi(1,2,3-dithiazolylidene) 11b into 3,6-diphenylisothiazolo[5,4-d]isothiazole 8b and scope of the reaction.
Table 2. Optimization of the ring transformation of (E)-4,4′-diphenyl-5,5′-bi(1,2,3-dithiazolylidene) 11b into 3,6-diphenylisothiazolo[5,4-d]isothiazole 8b and scope of the reaction.
Molecules 23 01257 i001
EntryRmmolThiophileSolventTimeYield 8Yields Ph3P = S or 14
(Equiv)(mL)(h)(%)(%)
1Ph0.05PhMe (5)298b (76)
2Ph0.05Ph3P (2)PhMe (5)38b (81)Ph3P = S (94)
3Ph0.05Ph3P (4)PhMe (5)2.58b (82)Ph3P = S (96)
4Ph0.05Et4NI (0.1)PhMe (5)178b (78)
5Ph0.05Et4NI (0.2)PhMe (5)28b (99) a
6Ph0.05Et4NI (2)PhMe (5)48b (98) a
7Ph0.05Et4NI (0.2)PhH (5)108b (nr) b
8Ph0.05Et4NI (0.2)PhCl (5)88b (72)14b (15) [23]
9Ph0.10Et4NI (0.2)PhMe (5)68b (95)14b (5) [23]
10Ph0.20Et4NI (0.2)PhMe (5)138b (63)14b (26) [23]
114-FC6H40.05Et4NI (0.2)PhMe (5)88c (69)14c (9) [20]
124-MeOC6H40.05Et4NI (0.2)PhMe (5)68d (99)
13thien-2-yl0.05Et4NI (0.2)PhMe (5)78e (92)14e (1) [48]
a Chromatography free, trace of elemental sulfur by TLC. b NR = no reaction.
Table 3. Crystallographic data for 8a, 8b, 8d and 11b.
Table 3. Crystallographic data for 8a, 8b, 8d and 11b.
8a8b8d11b
CCDC1840070184007118400731840072
Chemical formulaC4Cl2N2S2C16H10N2S2C18H14N2O2S2C16H10N2S4
Formula weight211.08294.38354.43358.50
Temperature (K)100120120120
Crystal systemMonoclinicMonoclinicMonoclinicOrthorhombic
Space groupC2/cP21/cP21/cPbca
a (Å)13.610(3)7.9372 (7)13.4370 (11)6.0657 (3)
b (Å)3.8300(7)5.3085 (5)3.9611 (3)15.7108 (9)
c (Å)13.843(3)15.6078 (14)14.6751 (12)16.1959 (9)
β (°)109.509(3)95.2366 (18)99.8510 (16)90
V (Å3)680.2(2)654.88 (10)769.57 (11)1543.42 (14)
Z/Z′4/0.52/0.52/0.54/0.5
dcalc (g cm3)2.0611.4931.5301.543
µ (Mo Kα)14.738.528.698.45
2Θmax58585858
Reflns. Collected/unique 3819/9074430/17298974/205317,657/2047
Observed reflns [I > 2σ(I)]822155617951883
Rint (I)0.02130.02130.02420.0128
R1 (F2)0.02050.02890.03080.0245
wR20.05100.07940.08730.0541
GOF1.0821.0441.0351.003
Δρminρmax−0.282/0.418−0.202/0.407−0.329/0.387−0.221/0.417

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MDPI and ACS Style

Konstantinova, L.S.; Baranovsky, I.V.; Strunyasheva, V.V.; Kalogirou, A.S.; Popov, V.V.; Lyssenko, K.A.; Koutentis, P.A.; Rakitin, O.A. The Conversion of 5,5′-Bi(1,2,3-dithiazolylidenes) into Isothiazolo[5,4-d]isothiazoles. Molecules 2018, 23, 1257. https://doi.org/10.3390/molecules23061257

AMA Style

Konstantinova LS, Baranovsky IV, Strunyasheva VV, Kalogirou AS, Popov VV, Lyssenko KA, Koutentis PA, Rakitin OA. The Conversion of 5,5′-Bi(1,2,3-dithiazolylidenes) into Isothiazolo[5,4-d]isothiazoles. Molecules. 2018; 23(6):1257. https://doi.org/10.3390/molecules23061257

Chicago/Turabian Style

Konstantinova, Lidia S., Ilia V. Baranovsky, Vlada V. Strunyasheva, Andreas S. Kalogirou, Vadim V. Popov, Konstantin A. Lyssenko, Panayiotis A. Koutentis, and Oleg A. Rakitin. 2018. "The Conversion of 5,5′-Bi(1,2,3-dithiazolylidenes) into Isothiazolo[5,4-d]isothiazoles" Molecules 23, no. 6: 1257. https://doi.org/10.3390/molecules23061257

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