Synthesis of 2-Mercapto-(2-Oxoindolin-3-Ylidene)Acetonitriles from 3-(4-Chloro-5H-1,2,3-Dithiazol-5-Ylidene)Indolin-2-ones

Alkylidene oxindoles are important functional moieties and building blocks in pharmaceutical and synthetic chemistry. Our interest in biologically active compounds focused our studies on the synthesis of novel oxindoles, bearing on the exocyclic double bond at the C8, CN, and S groups. Extending the potential applications of Appel’s salt, we developed a new synthetic approach by investigating the reactions of C5-substituted 2-oxindoles with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) to give original (Z)-3-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)indolin-2-one derivatives, and new 2-mercapto-(2-oxoindolin-3-ylidene)acetonitriles via a dithiazole ring-opening reaction. The work described in this article represents further applications of Appel’s salt in the conception of novel heterocyclic rings, in an effort to access original bioactive compounds. Fifteen new compounds were prepared and fully characterized.


Introduction
3-Alkenyl-2-oxindoles are an important class of heterocyclic compounds which are well established in the field of pharmaceutical chemistry, and they possess a large range of pharmacological activities [1][2][3][4][5][6]. For example, oxindole derivatives recently emerged as privileged scaffolds in the modulation of adenosine monophosphate-activated protein kinase (AMPK) [7], and 2-oxindole-based hydrazides are potent cytotoxic agents with apoptotic induction properties [8]. Substituted oxindoles are also very interesting building blocks for their role as starting materials toward more complex oxindole-based structures such as spirooxindoles [9,10]. Original piperidinoyl spirooxindoles can be obtained in very high yields and with excellent enantioselectivities via the hetero-Diels-Alder reaction between 2-aza-3-silyloxy-butadienes and alkylidene oxindoles [11]. It was also reported that donor or acceptor substituents at the ethylenic C8 carbon atom of isatylidenes constitutes an exceptional push-pull example, in which the electronic behavior of a fixed substituent on a double bond may be reversed by the electronic nature of the substituent at the opposite side of that double bond [12]. Palladium-catalyzed asymmetric allylic amination of racemic butadiene monoxide with oxindole derivatives was successfully developed using a chiral phosphoramidite-olefin hybrid ligand [13].
To generate the external double bond of the desired 3-alkenyl-indolin-2-one derivatives, we considered the electrophilic reactivity at the C1 position of Appel's salt toward the active methylene at the C3 position of indolin-2-one derivatives (Figure 2, 2).
To generate the external double bond of the desired 3-alkenyl-indolin-2-one derivatives, we considered the electrophilic reactivity at the C1 position of Appel's salt toward the active methylene at the C3 position of indolin-2-one derivatives (Figure 2, 2).  From the 1 H-NMR spectral data displayed, with only one set of aromatic signals in each case, it appeared that only one stereoisomer of each 3-(1,2,3-dithiazol-5-ylidene)indololin-2-one derivative ( Table 1, 3a-3d) was obtained. According to the work of Jeon et al. on several alpha-carbonylated 5alkylidene-1,2,3-dithiazoles, we assumed that the (Z)-stereoisomers were obtained [45][46][47][48][49][50]. The stereoselectivity depends on steric hindrance between the chlorine atom at the C4 position of the dithiazole ring, and the oxygen atom on the carbonyl lactame of the indolin-2-one moiety. Additionally, an attractive interaction, already described by Rees et al., could also be established between this oxygen atom and the sulfur atom at the S1 position of the dithiazole moiety, in light of the mesomer forms ( Figure 3) [45][46][47][48][49][50].  From the 1 H-NMR spectral data displayed, with only one set of aromatic signals in each case, it appeared that only one stereoisomer of each 3-(1,2,3-dithiazol-5-ylidene)indololin-2-one derivative ( Table 1, 3a-3d) was obtained. According to the work of Jeon et al. on several alpha-carbonylated 5-alkylidene-1,2,3-dithiazoles, we assumed that the (Z)-stereoisomers were obtained [45][46][47][48][49][50]. The stereoselectivity depends on steric hindrance between the chlorine atom at the C4 position of the dithiazole ring, and the oxygen atom on the carbonyl lactame of the indolin-2-one  We noticed that the one-dimensional (1D) NMR spectra of 3-(1,2,3-dithiazol-5-ylidene)indolin-2-one (Table 1, 3a-3d) displayed a strong downfield shift of the proton at the C4 position of the indolin-2-one core (8.19-9.13 ppm). Comparisons of the spectral data with those of the corresponding indolin-2-ones confirmed that the chemical shifts of this proton (H4) were displaced downfield by ~1 ppm, whereas the chemical shifts of the other aromatic protons were sensibly identical. This could be assigned to the proximity of the chlorine atom at the C4 position of the dithiazole ring. Similar observations were mentioned in the literature for (Z)-5-(2-oxoindolin-3-ylidene)thiazolidin-4-ones ( Figure 1, I) [26]. In these cases, X-ray diffraction analysis probed that the C=O of the thiazolidinone moiety interacted with the proton at the C4 position of the indolin-2-one core, causing a strong downfield shift of the proton in proximity [26,27].

Dithiazole
The assignment of stereochemistry to the dithiazoles, and the comparison of chemical shifts of 1 H-NMR of H4 of the dithiazole precusors ( Table 2, 3a-3d) and mercaptoacetonitrile derivatives ( Table 2, 4a-4d) showed that the (Z) isomer was obtained (Table 3).
According to the nature of the base used, it seems probable that, with sodium hydride, the reduction started via an attack on sulfur S1, leading to dithiazole ring opening followed by the release of sulfur ( 1 / 8 S 8 ) and the formation of the latent cyano group (Scheme 4, Path A). In Path B of Scheme 4, with methyl magnesium bromide, the products obtained could only be formed via an attack of the carbanion on the sulfur atom S2. This attack was followed by the generation of the carbonitrile. The 2-mercapto-2-(2-oxoindolin-3-ylidene)acetonitriles (Table 3, 4a-d) were finally obtained after the attack of a second carbanion on the sulfur atom S2, accompanied by the release of dimethyl sulfide (Scheme 4, Path B). with methyl magnesium bromide led only to dimers 5a and 5b (Tables 2 and 3). Whatever the base, no traces of the nitro dimer (Tables 2 and 3, 3d) were detected. The formation of these dimers seemed to be independent of the nature of the base used, suggesting a preponderant role of substituents on the aromatic ring. The assignment of stereochemistry to the dithiazoles, and the comparison of chemical shifts of 1 H-NMR of H4 of the dithiazole precusors ( Table 2, 3a-3d) and mercaptoacetonitrile derivatives ( Table 2, 4a-4d) showed that the (Z) isomer was obtained (Table 3). According to the nature of the base used, it seems probable that, with sodium hydride, the reduction started via an attack on sulfur S1, leading to dithiazole ring opening followed by the release of sulfur ( 1 /8 S8) and the formation of the latent cyano group (Scheme 4, Path A). In Path B of Scheme 4, with methyl magnesium bromide, the products obtained could only be formed via an attack of the carbanion on the sulfur atom S2. This attack was followed by the generation of the carbonitrile. The 2-mercapto-2-(2-oxoindolin-3-ylidene)acetonitriles (Table 3, 4a-d) were finally obtained after the attack of a second carbanion on the sulfur atom S2, accompanied by the release of dimethyl sulfide (Scheme 4, Path B). 5-Alkylidene-1,2,3-dithiazoles (Scheme 5, Table 4, 3a-3d) were then treated with two equivalents of supported triphenylphosphine as a nucleophile in dichloromethane. Dithiazoles (Scheme 5, Table  4, 3a-3d) were directly converted into 2-(2-oxoindolin-3-ylidene)acetonitriles (Scheme 5, Table 4, 6a-6d). Whatever the experimental conditions, unexpected open products bearing no sulfur atoms were always obtained in modest to good yields (27-82%), with no trace of mercaptoacetonitriles being 5-Alkylidene-1,2,3-dithiazoles (Scheme 5, Table 4, 3a-3d) were then treated with two equivalents of supported triphenylphosphine as a nucleophile in dichloromethane. Dithiazoles (Scheme 5, Table 4, 3a-3d) were directly converted into 2-(2-oxoindolin-3-ylidene)acetonitriles (Scheme 5, Table 4, 6a-6d). Whatever the experimental conditions, unexpected open products bearing no sulfur atoms were always obtained in modest to good yields (27-82%), with no trace of mercaptoacetonitriles being isolated (Scheme 4). A mixture of the two stereoisomers was obtained with the (E) isomer as the main compound for 6b-6d (Table 4). A substituent effect can be supposed since the 5-substituted oxindole-dithiazoles (Table 4, 3b-3d) afforded mainly the (E) isomer and the nude isomer, while 6a (Table 4) afforded mainly the (Z) isomer.

General Information
All commercially available chemicals and solvents were purchased from commercial sources, and used without further purification. 2-Oxindoles (Table 1, 2-oxindole 2a, 5-bromo-2-oxindole 2b, 5-chloro-2-oxindole 2c, and 5-nitro-2-oxindole 2d) were purchased from Sigma-Aldrich (Saint Quentin Fallavier, France). Anhydrous THF was purchased from Sigma-Aldrich, and was stored over 4 Å molecular sieves. All other solvents used were analytical grade purity. All reactions were carried in an inert atmosphere of argon, and were monitored by thin layer chromatography using Merck silica gel plates (60 F 254 /0.2 mm thickness). Purification through flash chromatography was performed using Merck silica gel 60 (63-200 µm; 70-230 mesh). 1 H-and 13 C-NMR spectra were recorded on a JEOL JNM-LA400 (Croissy Sur Seine, France) operating at 400 MHz ( 13 C 100 MHz) with tetramethylsilane as an internal standard in CDCl 3 , acetone-d 6 , or DMSO-d 6 solvent. Chemical shifts were given in ppm (δ), and coupling constants (J) were reported in Hertz. Proton-coupling patterns were described as singlet (s), doublet (d), triplet (t), or multiplet (m). High-resolution mass spectra (HRMS) were recorded on a Waters Q-TOF 2 (CRMPO, University of Rennes) or Waters Q-TOF instrument (CCA, University of La Rochelle). Melting points were determined in open capillaries on a Stuart melting point SMP3 digital melting point apparatus, and were uncorrected. IR spectra were recorded on a Perkin-Elmer Spectrum 100 IRTF instrument (Courtaboeuf-Les Ulis, France), and values were expressed in cm −1 .
Appel's salt (Scheme 2, 1; 4,5-dichloro-1,2,3-dithiazolium chloride; 15.76 mmol) was added to a solution of each appropriate 2-oxindole derivative (Scheme 2, 2a-d; 14.33 mmol) in CH 2 Cl 2 (20 mL). After a few minutes, the uncolored mixture turned to a dark red color, and was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, and the crude product was dissolved with acetone (a minimum of 30 mL), and then precipitated with water (300 mL). The heterogeneous mixture was filtered in a vacuum, and the red solid was washed three times with water (25 mL). This solid was finally dried over phosphorus pentoxide in a vacuum in a desiccator.  (Table 3, 4a-4d)

Path A with NaH
Sodium hydride at 60% in mineral oil (12 mmol) was added portionwise to a solution of each appropriate 5-alkylidene-1,2,3-dithiazole (Scheme 3, 3a-d; 6 mmol) in dry THF (15 mL). The dark red solution turned to dark yellow color after total consumption of the starting material. The solvent was evaporated under reduced pressure, and the crude product was quenched with brine (75 mL) and ethyl acetate (20 mL), before being extracted three times with ethyl acetate (200 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified through flash chromatography on a silica gel column (100% ethyl acetate).

Path B with CH 3 MgBr
Methyl magnesium bromine at 3 mol·L −1 (1.2 mmol) was added portionwise to a solution of each appropriate 5-alkylidene-1,2,3-dithiazole (Scheme 3, 3a-d; 0.6 mmol) in dry THF (4 mL). The dark red solution turned to a dark yellow color after total consumption of the starting material. The solvent was evaporated under reduced pressure, and the crude product was quenched with brine (15 mL) and ethyl acetate (10 mL), before being extracted three times with ethyl acetate (100 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified through flash chromatography on a silica gel column (100% ethyl acetate).   Supported triphenylphosphine at 2 mmol·g −1 (1.04 mmol) was added to a solution of each appropriate 5-alkylidene-1,2,3-dithiazole (Scheme 5, 3a-d; 0.52 mmol) in CH 2 Cl 2 (5 mL). The mixture was stirred at room temperature for 24 h, and filtered in a vacuum. The resin was washed three times with ethyl acetate (20 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified through flash chromatography on a silica gel column (ethyl acetate/petroleum ether). (Table 4, 6a) [61].

Conclusions
This work described novel examples of the importance of the 1,2,3-dithiazole skeleton in chemistry. It also confirmed the utility of Appel's salt in the conception of novel heterocyclic rings to access original potential bioactive compounds. The addition of Appel's salt to 2-oxindoles could be performed efficiently and stereoselectively. The corresponding 3-substituted oxindole derivatives could be subjected to selective ring opening, giving fast access to diversely functionalized oxindoles at position 3. Thanks to these methods, we easily generated two families of compounds-3-(1,2,3-dithiazolylidene)indololin-2-ones ( Table 2, 3a-d) and 2-mercapto-2-(2-oxoindolin-3-ylidene)acetonitriles (Table 3, 4a-d)-that could have interesting biological properties, such as protein kinase inhibition or antimicrobial properties. Optimization of the reaction conditions with triphenylphosphine should be performed in an effort to increase yields, and to learn more about stereoselectivity, since it seemed that most 2-(oxoindolin-3-ylidene)acetonitrile products ( Table 4, 6b-6d) were (E) isomers.
Author Contributions: V.T. and T.B. designed the research; B.L. and R.D. performed the experimental work, and participated equally to this work, and should be considered as primary co-authors. A.B. performed spectroscopic analysis. V.T. wrote the manuscript with the cooperation of T.B. and B.L. All authors discussed, edited, and approved the submitted version.