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Article

Synthesis of 2-Cyanobenzothiazoles via Pd-Catalyzed/Cu-Assisted C-H Functionalization/Intramolecular C-S Bond Formation from N-Arylcyanothioformamides †

by
Nathan Broudic
,
Alexandra Pacheco-Benichou
,
Corinne Fruit
* and
Thierry Besson
*
Univ Rouen Normandie, INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France
*
Authors to whom correspondence should be addressed.
†
This work is dedicated to the memory of Professor Charles W. Rees (1927–2006).
Molecules 2022, 27(23), 8426; https://doi.org/10.3390/molecules27238426
Submission received: 10 November 2022 / Revised: 21 November 2022 / Accepted: 24 November 2022 / Published: 1 December 2022
(This article belongs to the Special Issue Recent Advances in Heterocycles Synthesis)
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Abstract

:
We report herein on a catalytic system involving palladium and copper to achieve the cyclization of N-arylcyanothioformamides and the synthesis of 2-cyanobenzothiazoles. The C-H functionalization/intramolecular C-S bond formation reaction was achieved in the presence of air, using 2.0 equiv of an inorganic additive (KI). In many cases, the reaction led to a sole product regioselectively obtained in good yields, allowing the synthesis of a wide range of substituted 2-cyanobenzothiazole derivatives, providing valuable building blocks for the design of more complex heterocyclic or molecular labeling systems.

1. Introduction

Benzothiazole is a heterocyclic system originally discovered in marine natural molecules and also present in terrestrial specimens. Its numerous applications in therapeutics are regularly patented and published in comprehensive reviews describing their role against metabolic, inflammatory, neurodegenerative, viral and bacterial diseases [1,2,3,4,5,6]. In recent years, researchers have focused their efforts on the anti-cancer potential of benzothiazoles or their derivatives [7,8,9,10,11,12,13].
All these studies have shown that the biological activities of benzothiazoles are highly dependent on the nature and position of their substituents. The most favorable positions are carbon C2, C5 and C6 of the benzothiazole skeleton, and the number of functional groups can vary from 1 to 3 and range from a simple chemical function to more complex aliphatic or heterocyclic systems [1,2,3,4,5,6,7,8,9,10,11,12,13]. It is important to note that the benzothiazoles showing significant biological activity are mainly substituted at the C2 position of the thiazole ring. In terms of antiproliferative activity, the most remarkable compounds are benzothiazole derivatives substituted by a nitrogen atom (e.g., amine, urea, hydrazone and semicarbazone), sulfur atom (e.g., sulfanyl derivatives), or substituted aromatic group or a hetero-aromatic group (e.g., thiazole, pyridine, imidazole, pyrazole and oxazole). All these efforts led to numerous innovative synthetic routes for preparing such compounds [14,15,16].
Among this important heterocyclic family, 2-cyanobenzothiazoles (also called 1,3-benzothiazole-2-carbonitriles) are of particular interest. Despite some studies on their potential antiproliferative activity on cancer cells [17,18,19], research interest lies mainly in the ability of the carbonitrile function to react under nucleophilic attacks, thus allowing easy access to various functions such as amides, imidates, amidines, carboxylic acids and esters [20,21,22,23]. Moreover, it has been shown that the nitrile function can also be easily eliminated in acidic conditions (HCl or HBr) via a hydrolysis-decarboxylation sequence, allowing further arylation reactions at C2 via CH-activation methods [24,25]. In the last decade, 2-cyanobenzothiazoles substituted at the C6 position by a primary amine or hydroxyl group have become tools of choice in the development of click chemistry methods targeting cysteine residues under physiological and biocompatible conditions. This strategy was applied for the in situ assembly or self-assembly of biomolecules and nanostructures for various applications in drug targeting and delivery, specific labeling of peptides and biorthogonal ligation reactions [26,27,28,29,30,31,32,33].
There are several synthetic routes for preparing 2-cyanobenzothiazoles in the literature [34,35,36,37,38,39,40,41,42,43,44,45]. The seminal work of White and colleagues outlined their synthesis, mainly focusing on luciferin-based derivatives that are mono-substituted at the C6 position with electron-donating groups (OMe, OH or NH2) [34,35]. Most of the time, the multi-step syntheses included in the final step the Rosemund-von Braun and Sandmeyer reactions from 2-iodo-, 2-chloro- and 2-amino-6-substituted benzothiazoles [36,37,38], respectively, involving toxic cyanide as a reactant. Alternatively, 6-methoxy-1,3-benzothiazole-2-carboxamide was used as a precursor to produce the expected cyanated products [39]. Less conventional synthetic routes have also been described in studies on the cyanation of heterocyclic compounds. In most cases, only unsubstituted 2-cyanobenzothiazole was reported as an example of the application of the studied methodology [40,41,42,43,44,45].
One of the most popular methods described in the last 10 years for the synthesis of 2-cyanobenzothiazoles was inspired by the work of Rees and colleagues [46,47,48]. In the early 1990s, they studied the chemistry of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) [49] and described the synthesis of 2-cyanated benzothiazoles (C) by thermolysis of 5-N-arylimino-4-chloro-1,2,3-dithiazoles (B) [50,51], obtained by the reaction of aromatic amines (A) with Appel salt (Figure 1).
These studies demonstrated that strong electron-withdrawing groups on the starting anilines can modify the cyclization process and lead to a large number of undesired products such as cyanoimidoyl chloride (D in Figure 1). Seeking to overcome the influence of substituents, the same group described the copper(I)-mediated and regioselective cyclization of imino-1,2,3-dithiazoles (B’) resulting from the condensation of substituted o-bromoanilines with Appel salt [52]. These efficient reactions were rapidly performed at atmospheric pressure with a focused microwave reactor or under traditional heating, albeit for a longer time. All these studies have outlined the difficulties in obtaining the relevant o-brominated reagents to provide the target 2-cyanobenzothiazoles.
Some years later, drawing on the preceding work by Doi on the synthesis of 2-arylbenzothiazoles by the cyclization of thiobenzanilides [53,54], Prescher and colleagues, described a convenient method for preparing 6-methoxybenzothiazole-2-carbonitrile (Figure 1), allowing three-step access to bioluminescent luciferin derivatives [55,56]. In these studies, the condensation of p-anisidine with Appel salt led to the corresponding 4-chloro-N-(4-methoxyphenyl)-5H-1,2,3-dithiazol-5-imine, which was converted to its cyanothioformamide analogue (also called cyanothioformanilide) (E in Figure 1). Benzothiazole ring closure was performed with palladium chloride (PdCl2) and copper iodide (CuI) as catalysts with tetrabutylammonium bromide (TBAB) as an organic additive, in a mixture of DMSO/DMF (1:1, v/v) as the solvent [55,56]. Recently, Moussa et al. investigated the efficiency of I2-DMSO as an oxidative system and described the unexpected conversion of some N-arylcyanothioformamides into 2-cyanobenzothiazoles (five examples, Figure 1) [57].
For the last 10 years, our group investigated the chemical application of Appel Salt and its 5-N-arylimino-4-chloro-1,2,3-dithiazole derivatives for fusing the 2-cyanobenzothiazole motif on pyrimidine or pyrimidinone systems, and synthesizing bioactive thiazoloquinazolines and quinazolinones, which are able to affect the activity of kinases involved in neurodegenerative diseases (Alzheimer’s disease, Down’s syndrome) and cancers [58,59,60,61]. Recently a new strategy in our molecular and biological targets incited us to develop more practical and efficient general synthetic protocols. It appeared relevant and useful to allow easy access to diversely substituted and functionalized 2-cyanobenzothiazole derivatives. The present study thoroughly investigates a convenient palladium-catalyzed and copper-assisted method for the synthesis of a large array of these compounds and improves upon the existing literature. It also aims at exploring the regioselectivity of the thiazole ring closure under the steric or electronic influence of substituents present on the starting anilines. For the first time, a reaction mechanism is suggested in adequation with the data obtained (Figure 1).

2. Results and Discussion

In the present study, preliminary experiments were carried out to explore the synthetic route to the 6-methylbenzo[d]thiazole-2-carbonitrile 4a. p-Toluidine 1a was condensed with Appel salt (1.1 equiv) in the presence of pyridine (2.0 equiv) in dichloromethane (DCM), at room temperature (r.t.) for 1 h, to give the imino-1,2,3-dithiazole 2a. The compound 2a was then treated by 3 equiv of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) [62] to produce the corresponding N-(4-methylphenyl)cyanothioformamide 3a in convenient yields (46%) (see Table 1).
In a first attempt, based on the experimental conditions described by Doi [53,54] and Prescher [55,56]; 3a was solubilized in DMSO/DMF (1:1, v/v, [0.025 or 0.050 M]) and heated at 120 °C for 4 h in the presence of 10 or 20 mol% of PdCl2, 50 mol% of CuI and 2 equiv of tetrabutylammonium bromide (TBAB), as depicted in Table 1.
The best result was obtained with 20 mol% of PdCl2 and a starting molar concentration of 0.025 M in the solvent mixture. Under these conditions, the expected benzothiazole 4a was obtained with a 49% yield (entry 4). Expecting improvement, TBAB was replaced by tetrabutylammonium iodide (TBAI) and produced 4a a similar yield (51%).
In the preceding work [53,54], Doi and colleagues discovered that the addition of an inorganic additive such as CsF led to a significant improvement in the C-H functionalization/intramolecular C-S bond formation reaction from thiobenzanilides. We, therefore, replaced TBAB by 2 equiv of CsF, but this provided 4a in only a 15 % yield (entry 1 in Table 2). Based on these preliminary results, inorganic additives in place of TBAB or CsF were screened. Table 2 reports our results with various inorganic salts (2.0 equiv) added to the reaction mixture. The other reactants and solvent proportions remained unchanged.
Among the salts tested, cesium derivatives (CsF and CsI) were found to be the least effective additives (entries 1 and 2) while sodium, potassium and lithium salts produced good results, producing the desired 6-methyl-2-cyanobenzothiazole 4a in moderate to good yields (53–70%) (entries 3-5, 7 and 9), except in the case of KF and LiCl, which led to yields of 16 and 33%, respectively (entries 6 and 8). In our case, KI gave the best results leading to 4a with a 70% yield (entry 5). Atmospheric oxygen plays a crucial role since an inert atmosphere (argon) gave a lower yield of 23% (see footnote 2 for entry 5). Increasing the quantity of KI (3.0 equiv) also had a negative effect on the yield of the reaction, which fell to 39% (see footnote 3 for entry 5). It is noteworthy that in the optimizing experiments described by Doi et al. [53], LiBr gave the expected product in the same yield as that obtained with TBAB. In our case, LiBr allowed the synthesis of 4a in only a 53% yield (entry 7). Entry 10 confirms that the additive is required to obtain 4a in a good yield.
To complete the optimization of the reaction conditions, various sources of palladium and copper were also tested. Solvent and co-solvent were also investigated, as depicted in Table 3.
None of the new conditions tested improved the reaction efficiency except PdBr2, which led to a similar yield to PdCl2 (entry 2). Using Pd(OAc)2 and Pd2dba3 drastically decreased the quantity of 4a obtained (22 and 7%, respectively) (entries 3 and 4). The absence of a palladium source in the reaction mixture gave no reaction (entry 5) while the lack of copper led to a lower yield (41% instead of 70%) (entry 9), confirming the need for these components in the chemical equation. Out of all the solvents tested, the initial mixture of DMSO/DMF in equal proportions remained the best for this reaction (entry 1 compared to entries 10, 11 and 12).
Table 4 also reports the results obtained when initial amounts of palladium chloride (PdCl2) and copper iodide (CuI) were optimized, as well as the starting molar concentration [c] in the solvent mixture. It confirms that heating the starting cyanothioformamide 3a at 120 °C for 4 h in DMSO/DMF (1:1, v/v; [0.025 M]), in the presence of 20 mol% PdCl2, 50 mol% CuI and 2 equiv of potassium iodide (KI), was the most efficient method for the synthesis of 4a (entry 1). In all cases, changing the initial concentration of PdCl2 or CuI, or the amount of solvent, led to lower yields (entries 2, 3, 4 and 5).
Considering our experience investigating the role of microwaves in the thermal activation of chemical reactions [63], a series of tests were performed in a microwave reactor operating at atmospheric pressure. Compound 4a was synthesized by applying the same operating parameters (quantities of reagents, solvent, temperature) as those described above. The programmed temperature was controlled by an external infrared pyrometer, which allowed feedback control of the power input in the cavity. A TLC control showed the disappearance of the reagents after 1 h of irradiation, and no change was observed on prolonged heating. Compound 4a was isolated in a lower yield (57%) than under the standard thermal conditions (70%).
With the optimized conditions identified, the scope of N-arylcyanothioformamides 3 was explored to generate a valuable array of variously substituted 2-cyanobenzothiazoles. As described above for 3a, all N-arylcyanothioformanilides 3 were obtained using a two-step procedure in which starting anilines 1 were stirred with Appel salt (1.1 equiv) and pyridine (2.0 equiv) in dichloromethane (DCM), at r.t. for 1 h, to give the corresponding imino-1,2,3-dithiazoles 2, which were then treated by 3 equiv of 1,8-diazabicyclo [5.4.0] undéc-7-ene (DBU) in DCM at r.t. for 15 min (Scheme 1) [62].
Yields are reported in Table 5; for detailed procedures and physicochemical characterization see the Supplementary Materials. Note that the sequential one-pot process previously described by Prescher et al. for the preparation of 3f (4-OMe) and 3j (4-NO2) [56] was not applicable to this range of anilines.
Firstly, 2-, 3- or 4-mono-substituted cyanothioformamides 3a-p were transformed into the corresponding 4-, 5- and 6-mono-substituted 2-cyanobenzothiazoles 4a-p according to the already optimized C-H functionalization/intramolecular C-S bond formation reaction (Scheme 2).
The yields obtained with substituents positioned at C6 were quite good, ranging from 41% for the bis-cyanated derivative 4h to 71% for 4f with an electron donor group (e.g., OMe). The electronic effect of the substituents at the C3 position of the starting cyanothioformamide slightly affected the yields in the resulting C5-substituted 2-cyanobenzothiazoles such as 4k, 4l and 4m. Nevertheless, the 5-methoxybenzothiazole-2-carbonitrile 4k was then obtained in a similar yield as that of its 6-substituted isomer 4f (68 and 71%, respectively). Notably, whatever the N-cyanothioformamide reagent, no C4-substituted 2-cyanobenzothiazole regioisomer was obtained, suggesting a regiospecific cyclization process. Moreover, despite a deactivating effect on the aromatic ring, the ethyl carboxylate group was found to be compatible and 2-cyanobenzothiazoles 4j and 4m were isolated in good yields (75 and 57%, respectively). The yields obtained for the 5- and 6-nitrobenzothiazole-2-carbonitriles 4l and 4i produced a more significant difference of 30 and 51%, respectively.
To increase the range of 2-cyanobenzothiazoles, derivatives di-substituted in the 5,6—, 4,5- and 4,6-positions (compounds 4q-4x) were prepared from the corresponding N-arylcyanothioformamides 3q-3x, difunctionalized in the 3,4-, 2,3- and 2,4 -positions (Scheme 3).
Di-substituted benzothiazoles in positions 5 and 6 were obtained in good (67% for 4t) to excellent yields (e.g., 96 and 94% for 4q and 4r, respectively). In these cases, the substituents were mainly activating groups while a bromide in p-position for the nitrogen atom led to a decrease in the yield (71% for 4s compared with 96% for 4q). This result is in accordance with those described in Scheme 1 for 4a and 4e with yields of 70 and 54%, respectively. Microwave-assisted synthesis of 4q and 4s was also tested and confirmed the results previously obtained for 4a.
The synthesis of 4,5-di-substituted 2-cyanobenzothiazoles (4v, 4w and 4x) proved to be more difficult and yields were lower than those obtained with the 5,6-disubstituted compounds. However, these results are close to those obtained in the synthesis of benzothiazoles 4n-4p from cyanothioformanilides 3n-3p, which are substituted in position 2. These results suggest a significant steric effect when substituents are in the C2 position of the reagent. This effect is apparently counterbalanced by the electron-donor effect of the substituents in the C4 position, as shown by the data obtained for the synthesis of 2-cynobenzothiazoles 4z and 4aa.
To complete our study, access to 5,7- and 4,7-substituted 2-cyanobenzothiazoles (4ab-4ag) was studied from the corresponding cyanothioformanilides (3ab-3ag) (Scheme 4).
Compounds 4ab and 4ac were obtained in good yields of 59 and 65%, respectively. In contrast, when the reaction was produced using dissymmetric cyanothioformamides on the C3 and C5 positions (3ad and 3ae), a mixture of regioisomers was obtained in an about 30% yield in both cases. The benzothiazoles 4ae’ and 4ae’’ were separated by flash column chromatography and isolated in 11 and 24% yields. However, compounds 4ad’ and 4ad’’ could not be separated regardless of the techniques used. The intramolecular C-S bond formation sequence predominantly occurred on the side of the electron-donor substituent with a ratio of 2:1 to the other partner. Unfortunately, the developed method failed to cyclize the cyanothioformamides disubstituted in C2 and C5 (3af and 3ag in Scheme 4).
Cyanobenzothiazole-2-carbonitrile 4af was obtained in only a 22% yield when KI was replaced by 2.0 equiv of LiBr.
This result suggests that depending on the reagents, the size of the inorganic additive may influence the yield of this regiospecific reaction. In the case of 4a (Table 2), no steric constraints were present and KI was more efficient than LiBr. In contrast, for the cyanothioformamide 3af, steric hindrance prevented KI from playing its role in the reaction. Nevertheless, this yield was still lower than the one previously obtained by our group (58%) when compound 2af was subjected to microwave-assisted thermolysis at 150 °C in N-methylpyrrolidinone (NMP) [51]. Notably, Prescher also observed the same drawback and finally heated 2,5-disubstituted cyanothioformamides at 170 °C in sulfolane to obtain the attempted 4-bromo-7-methyl-benzothiazole-2-carbonitrile derivatives, also in low yields (10–20%) [32].
Scheme 5 depicts the suggested mechanism, based on these results and the literature data [63,68].
The reaction is most likely initiated by the base-assisted formation of the Cu(I) thioamidate (I), favoring the coordination of Pd(II) with the sulfur atom to form the intermediate (II). Then, a deprotonative metalation step occurs, forming a sterically hindered transition state driving the regioselectivity (III), to obtain the palladacycle (IV), which undergoes reductive elimination, leading to the desired 2-cyanobenzothiazole 4 and Pd(0), which can be reoxidized by atmospheric oxygen.

3. Materials and Methods

3.1. General Information

All reagents were purchased from commercial suppliers and used without further purification. All reactions were monitored by thin-layer chromatography with aluminum plates (0.25 mm) precoated with silica gel 60 F254 (Merck KGaA, Darmstadt, Germany). Visualization was performed with UV light at a wavelength of 254 nm. Purifications were conducted with a flash column chromatography system (PuriFlash, Interchim, Montluçon, France) using stepwise gradients of petroleum ether (also called light petroleum) (PE) and dichloromethane (DCM) as the eluent. Melting points were measured with an SMP3 Melting Point instrument (STUART, Bibby Scientific Ltd., Roissy, France) with a precision of 1.5 °C. IR spectra were recorded with a Spectrum 100 Series FTIR spectrometer (PerkinElmer, Villebon S/Yvette, France). Liquids and solids were investigated with a single-reflection attenuated total reflectance (ATR) accessory; the absorption bands are given in cm−1. NMR spectra (1H, 13C and 19F) were acquired at 295 K using an AVANCE 300 MHz spectrometer (Bruker, Wissembourg, France) at 300, 75 and 282 MHz. Coupling constant J was in Hz and chemical shifts were given in ppm. Mass (ESI, EI and field desorption (FD) were recorded with an LCP 1er XR spectrometer (WATERS, Guyancourt, France). Mass spectrometry was performed by the Mass Spectrometry Laboratory of the University of Rouen.

3.2. Chemistry

3.2.1. Synthesis of N-Arylimino-1,2,3-dithiazoles (2) and N-Arylcyanothioformamides (3)

All N-arylcyanothioformanilides 3 were obtained using a two-step procedure as described in the main text (Scheme 1). Detailed procedures and physicochemical characterization of products are available in Supplementary Materials (Sections S2–S6 for 2 series and S6–S11 for 3 series).

3.2.2. Synthesis of 2-Cyanobenzothiazoles (4)

General procedure: To a stirred solution of N-arylcyanothioformamide (3, 0.5 mmol) in an anhydrous mixture of DMF/DMSO (1:1, v/v) (20 mL, 0.025M) were successively added PdCl2 (20 mol %, 17.7 mg, 0.05 mmol), CuI (50 mol %, 47.6 mg, 0.25 mmol) and KI (2.0 equiv, 166 mg, 1.0 mmol). The resulting mixture was stirred at 120 °C for 4 h after which it was diluted with AcOEt and washed with water (3 times) and brine (1 time), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on silica gel with PE/CH2Cl2 (50:50 to 0:100, v/v) as eluent to produce the desired product.
Some compounds of the 4 series (4a, 4b, 4f, 4o, 4i, 4k, 4l, 4n, 4p, 4r, 4u and 4af) were randomly described in studies cited in this paper [44,47,48,51,57,69]. To complete data sometimes uneasy to find in the literature, all compounds 4 were fully characterized. The general procedure of their synthesis and physicochemical characterization are described below. 1H NMR and 13C NMR spectra of these products are available in the Supplementary Materials (Sections S12–S47).
6-Methylbenzo[d]thiazole-2-carbonitrile (4a) [51]. Brown powder (0.061 g, 70%), m.p. 92–93 °C. IR (neat) νmax: 2916, 2225 (CN), 1597, 1505, 1481, 1258, 1232, 1119, 1017, 821, 489, 432 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J = 8.5 Hz, 1H), 7.76 (dt, J = 1.7, 0.8 Hz, 1H), 7.46 (ddd, J = 8.5, 1.7, 0.8 Hz, 1H), 2.56 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 150.55, 139.55, 135.71, 135.32, 129.82, 124.74, 121.23, 113.17, 21.84. HRMS (EI+) m/z, calcd for C9H7N2 [M]+: 175.0330, found: 175.0341.
Benzo[d]thiazole-2-carbonitrile (4b) [50]. Pale yellow powder (0.051 g, 61%), m.p. 76–77 °C. IR (neat) νmax: 2917, 2228 (CN), 1466, 1421, 1317, 1147, 1132,759, 727, 408 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.28–8.18 (m, 1H), 8.03–7.94 (m, 1H), 7.70–7.59 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 152.38, 136.66, 135.45, 128.77, 128.07, 125.42, 121.92, 113.11. HRMS (EI+) m/z, calcd for C8H5N2S [M]+: 161.0185, found: 161.0173.
6-Fluorobenzo[d]thiazole-2-carbonitrile (4c) [47]. White solid (0.058 g, 65%), m.p. 108–109 °C. IR (neat) νmax: 3048, 2231 (CN), 1597, 1559, 1493, 1203, 1134, 820 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.20 (ddd, J = 9.2, 4.8, 0.5 Hz, 1H), 7.66 (ddd, J = 7.7, 2.5, 0.5 Hz, 1H), 7.41 (ddd, J = 9.1, 8.6, 2.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 162.67 (d, J = 252.6 Hz), 149.10 (d, J = 1.7 Hz), 136.77 (d, J = 11.7 Hz), 136.38 (d, J = 3.8 Hz), 126.83 (d, J = 9.8 Hz), 117.55 (d, J = 25.3 Hz), 112.76, 108.05 (d, J = 27.4 Hz). 19F NMR (282 MHz, CDCl3) δ –109.30 (s). HRMS (EI+) m/z, calcd for C8H4N2FS [M]+: 179.0079, found: 179.0080.
6-Chlorobenzo[d]thiazole-2-carbonitrile (4d) [44]. White solid (0.069 g, 71%), m.p. 123–124 °C. IR (neat) νmax: 2228 (CN), 1467, 1311, 1147, 832, 419 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.14 (dd, J = 8.8, 0.5 Hz, 1H), 7.98 (dd, J = 2.1, 0.5 Hz, 1H), 7.62 (dd, J = 8.8, 2.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 150.91, 137.06, 136.58, 135.41, 129.25, 126.18, 121.51, 112.73. HRMS (EI+) m/z, calcd for C8H4N2S35Cl [M]+: 194.9784, found: 197.9775.
6-Bromobenzo[d]thiazole-2-carbonitrile (4e) [69]. White solid (0.064 g, 54%), m.p. 141–142 °C. IR (neat) νmax: 2231 (CN), 1581, 1467, 1388, 1307, 1146, 1076, 85, 414 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.15 (dd, J = 1.9, 0.5 Hz, 1H), 8.08 (dd, J = 8.9, 0.5 Hz, 1H), 7.76 (dd, J = 8.9, 1.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 151.13, 137.00, 136.88, 131.85, 126.35, 124.45, 123.18, 112.67. HRMS (EI+) m/z, calcd for C8H4N2S79Br [M]+: 238.9279, found: 238.9283.
6-Methoxybenzo[d]thiazole-2-carbonitrile (4f) [51]. Brownish powder (0.068 g, 71%), m.p. 123–124 °C. IR (neat) νmax: 2844, 2225 (CN), 1597, 1505, 1446, 1016, 821 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, J = 9.1, 0.5 Hz, 1H), 7.36 (d, J = 2.5 Hz, 1H), 7.26–7.22 (dd, J = 9.1, 2.5 Hz, 1H), 3.93 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.60, 147.03, 137.58, 133.46, 125.98, 118.67, 113.35, 103.10, 56.11. HRMS (EI+) m/z, calcd for C9H7N2OS [M]+: 191.0279, found: 191.0287.
6-Trifluoromethylbenzo[d]thiazole-2-carbonitrile (4g). Pale orange solid (0.058 g, 51%), m.p. 48–49 °C. IR (neat) νmax: 2228 (CN), 1475, 1318, 1160, 1124, 1077, 882, 836, 705, 650 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.35 (dt, J = 8.7, 0.8 Hz, 1H), 8.32 (dt, J = 1.8, 0.8 Hz, 1H), 7.89 (dd, J = 8.7, 1.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 154.07, 139.76, 135.44, 130.88 (q, J = 33.2 Hz), 124.99 (q, J = 3.3 Hz), 119.87 (q, J = 4.3 Hz), 123.64 (q, J = 273.0 Hz), 112.47. 19F NMR (282 MHz, CDCl3) δ -60.43 (s). HRMS (EI+) m/z, calcd for C9H4N2F3S [M]+: 229.0047, found: 229.0057.
6-Cyanobenzo[d]thiazole-2-carbonitrile (4h). White solid (0.038 g, 41%), m.p. 178–179 °C. IR (neat) νmax: 3090, 2227 (CN), 1466, 1398, 1316, 1248, 1141, 834, 615, 487 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.38–8.32 (m, 2H), 7.90 (dd, J = 8.6, 1.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 154.26, 140.71, 135.72, 130.79, 127.01, 126.41, 117.65, 112.60, 112.22. HRMS (EI+) m/z, calcd for C9H3N3S [M]+: 185.0048, found: 185.0045.
6-Nitrobenzo[d]thiazole-2-carbonitrile (4i). White solid (0.050 g, 51%), m.p. 166–167 °C. IR (neat) νmax: 3096, 2236 (CN), 1565, 1509, 1342, 1328, 1144, 1107, 902, 832, 754 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.96 (dd, J = 2.2, 0.6 Hz, 1H), 8.52 (dd, J = 9.1, 2.2 Hz, 1H), 8.38 (dd, J = 9.1, 0.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 155.44, 147.39, 141.90, 135.71, 126.19, 123.23, 118.70, 112.13. HRMS (EI+) m/z, calcd for C8H3N3O2S [M]+: 204.9946, found: 204.9938.
Ethyl 2-cyanobenzo[d]thiazole-6-carboxylate (4j). Pale brown solid (0.065 g, 75%), m.p. 139–140 °C. IR (neat) νmax: 2219 (CN), 1709, 1273, 1131, 1022, 833, 768, 725, 479, 415, 389 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.72 (dd, J = 1.5, 0.8 Hz, 1H), 8.31 (dd, J = 8.7, 1.5 Hz, 1H), 8.27 (dd, J = 8.7, 0.8 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.35, 154.80, 139.67, 135.32, 130.77, 128.89, 125.22, 124.11, 112.69, 62.01, 14.44. HRMS (EI+) m/z, calcd for C9H7N2OS2 [M]+: 233.0385, found: 233.0380.
5-Methoxybenzo[d]thiazole-2-carbonitrile (4k) [48]. Pale yellow powder (0.065 g, 68%), m.p. 93–94 °C. IR (neat) νmax: 2230 (CN), 1603, 1473, 1413, 1338, 1276, 1168, 1019, 832, 814, 470, 413 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 9.0 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.28 (dd, J = 9.0, 2.5 Hz, 1H), 3.92 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.38, 154.03, 127.45, 122.04, 120.29, 113.30, 106.24, 55.91. HRMS (EI+) m/z, calcd for C9H7N2OS2 [M]+: 191.0279, found: 191.0289.
5-Nitrobenzo[d]thiazole-2-carbonitrile (4l) [48]. White solid (0.031 g, 30%), m.p. 196–197°C. IR (neat) νmax: 3095, 2244 (CN), 1599, 1572, 1512, 1339, 1137, 1077, 1056, 908, 827, 738, 710, 529, 494, 411 cm−1. 1H NMR (300 MHz, DMSO-d6) δ 9.11–9.02 (m, 1H), 8.64–8.58 (m, 1H), 8.50 (dt, J = 9.1, 2.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 151.01, 147.51, 141.70, 141.67, 124.81, 122.34, 119.82, 112.88. HRMS (EI+) m/z, calcd for C8H4N3O2S [M]+: 206.0024, found: 206.0038.
Ethyl 2-cyanobenzo[d]thiazole-5-carboxylate (4m). White solid (0.066 g, 57%), m.p.: 113–114 °C. IR (neat) νmax: 3099, 2999, 2981, 2924, 2231 (CN), 1704, 1602, 1541, 1449, 1360, 1323, 1281, 1228, 1137, 1088, 1016, 757 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.90 (dd, J = 1.6, 0.7 Hz, 1H), 8.32–8.27 (m, 1H), 8.05 (dd, J = 8.6, 0.6 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 165.56, 152.26, 139.49, 138.14, 130.94, 129.08, 126.98, 121.91, 112.71, 61.90, 14.44. HRMS (EI+) m/z, calcd for C11H9N2O2S [M]+: 233.0385, found: 233.0390.
4-Chlorobenzo[d]thiazole-2-carbonitrile (4n). White powder (0.037 g, 38%), m.p. 171–172 °C. IR (neat) νmax: 2227 (CN), 1579, 1543, 1457, 1314, 1148, 1095, 818, 780, 739, 646 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.90 (dd, J = 8.0, 1.1 Hz, 1H), 7.69 (dd, J = 8.0, 1.1 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 149.68, 137.44, 136.86, 130.64, 129.42, 128.34, 120.47, 112.64. HRMS (EI+) m/z, calcd for C8H4N2S35Cl [M]+: 194.9794, found: 197.9786.
4-Bromobenzo[d]thiazole-2-carbonitrile (4o). White powder (0.034 g, 28%), m.p. 178–179 °C. IR (neat) νmax: 2229 (CN), 1537, 1456, 1312, 1147, 1077, 871, 778, 738, 640 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.94 (dd, J = 8.2, 1.0 Hz, 1H), 7.87 (dd, J = 7.7, 1.0 Hz, 1H), 7.50 (dd, J = 8.2, 7.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 150.87, 137.21, 136.29, 131.66, 129.63, 121.11, 119.25, 112.65. HRMS (EI+) m/z, calcd for C8H4N2S79Br [M]+: 238.9279, found: 238.9286.
4-Methoxybenzo[d]thiazole-2-carbonitrile (4p). Pale brown powder (0.045 g, 47%), m.p. 124–125 °C. IR (neat) νmax: 2225 (CN), 1559, 1475, 1457, 1330, 1270, 1193, 1129, 1035, 776, 744, 666 cm−1.1H NMR (300 MHz, CDCl3) δ 7.64–7.50 (m, 2H), 7.03 (dd, J = 7.6, 1.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 154.99, 143.18, 137.33, 134.93, 130.29, 113.48, 113.06, 107.84, 56.47. HRMS (EI+) m/z, calcd for C9H7N2OS [M]+: 191.0279, found: 191.0277.
5,6-Dimethylbenzo[d]thiazole-2-carbonitrile (4q). Pale brown solid (0.090 g, 96%), m.p. 136–137 °C. IR (neat) νmax: 3045, 2980, 2949, 2924, 2228 (CN), 1610, 1432, 1261, 1149, 865, 429 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J = 1.0 Hz, 1H), 7.71 (d, J = 1.0 Hz, 1H), 2.44 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 151.28, 139.26, 137.93, 135.07, 133.14, 124.98, 121.38, 113.41, 77.58, 77.16, 76.74, 20.63, 20.37. HRMS (EI+) m/z, calcd for C10H9N2S [M]+: 189.0486, found: 189.0485.
5,6-Dimethoxybenzo[d]thiazole-2-carbonitrile (4r) [57]. Pale brown solid (0.104 g, 94%), m.p. 160–161 °C. IR (neat) νmax: 2222 (CN), 1494, 1439, 1418, 1282, 1230, 1207, 1170, 1059, 846, 813 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 7.29 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H) 13C NMR (75 MHz, CDCl3) δ 151.84, 151.10, 147.29, 133.47, 128.84, 113.49, 105.31, 101.37, 56.59, 56.39. HRMS (EI+) m/z, calcd for C10H9N2O2S [M]+: 221.0385, found: 221.0395.
6-Bromo-5-methylbenzo[d]thiazole-2-carbonitrile (4s). White solid (0.090 g, 71%), m.p. 182–183 °C. IR (neat) νmax: 3055, 2957, 2920, 2229 (CN), 2116, 1770, 1689, 1519, 1420, 1297, 1168, 1138, 887, 834, 419 cm−1. 1H NMR (300 MHz, CDCl3) δ 8.18 (s, 1H), 8.08 (d, J = 1.1 Hz, 1H), 2.59 (d, J = 0.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 151.94, 138.68, 136.94, 134.03, 126.59, 126.09, 124.80, 112.90, 23.63. HRMS (EI+) m/z, calcd for C9H6N2S79Br [M]+: 252.9435, found: 252.9446.
[1,3]Dioxolo [4′,5′:4,5]benzo [1,2-d]thiazole-6-carbonitrile (4t). White solid (0.068 g, 67%), m.p. 190–191 °C. IR (neat) νmax: 3038, 2917, 2225 (CN), 1472, 1427, 1274, 1144, 1031, 937, 869, 797, 485, 414 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.53 (s, 1H), 7.28 (s, 1H), 6.15 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 150.40, 149.97, 148.20, 134.01, 130.24, 113.31, 104.72, 102.88, 98.32. HRMS (EI+) m/z, calcd for C9H5N2O2S [M]+: 205.0072, found: 205.0067.
6,7-Dihydro-[1,4]dioxino [2′,3′:4,5]benzo [1,2-d]thiazole-2-carbonitrile (4u). Pale brown solid (0.094 g, 86%), m.p. 179–180 °C. IR (neat) νmax: 2230 (CN), 1481, 1302, 1176, 1063, 928, 873, 809, 709 cm−1.1H NMR (300 MHz, CDCl3) δ 7.66 (s, 1H), 7.37 (s, 1H), 4.36 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 147.53, 146.42, 145.27, 134.60, 129.03, 113.35, 111.93, 108.15, 64.62, 64.18. HRMS (EI+) m/z, calcd for C10H7N2O2S [M]+: 219.0228, found: 219.0220.
4,5-dimethylbenzo[d]thiazole-2-carbonitrile (4v). White solid (0.035 g, 37%), m.p. 93–94 °C. IR (neat) νmax: 3667, 2988, 2230 (CN), 1551, 1461, 1067, 880, 808, 565 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 2.72 (s, 3H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 152.56, 136.11, 135.01, 133.86, 132.86, 131.28, 118.28, 113.54, 19.71, 15.02. HRMS (EI+) m/z, calcd for C10H9N2S [M]+: 189.0486, found: 189.0499.
4,5-Dichlorobenzo[d]thiazole-2-carbonitrile (4w). White powder (0.056 g, 49%), m.p. 171–172 °C. IR (neat) νmax: 3070, 2232 (CN), 1527, 1461, 1435, 1384, 1303, 1232, 1186, 1155, 1101, 927, 814, 676, 611, 573 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 150.87, 138.74, 134.70, 133.22, 130.56, 129.25, 120.29, 112.34. HRMS (EI+) m/z, calcd for C8H3N2S35Cl2 [M]+: 228.9394, found: 228.9393.
5-Chloro-4-methylbenzo[d]thiazole-2-carbonitrile (4x). White powder (0.033 g, 32%), m.p. 129–130 °C. IR (neat) νmax: 2232 (CN), 1553, 1450, 1377, 1308, 1197, 1155, 1119, 1017, 807 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.74 (dq, J = 8.7, 0.7 Hz, 1H), 7.61 (dd, J = 8.7, 0.7 Hz, 1H), 2.84 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 152.99, 136.76, 134.13, 133.98, 133.67, 129.93, 119.43, 113.00, 15.96. HRMS (EI+) m/z, calcd for C9H6N2S35Cl [M]+: 208.9940, found: 208.9943.
4,6-Difluorobenzo[d]thiazole-2-carbonitrile (4y) [47]. White powder (0.034 g, 35%), m.p. 100–101°C. IR (neat) νmax: 1620, 1519, 1471, 1422, 1288, 1258, 1118, 855, 839, 539 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.50 (ddd, J = 7.4, 2.3, 1.3 Hz, 1H), 7.17 (ddd, J = 9.7, 9.0, 2.3 Hz, 1H). 19F NMR (282 MHz, CDCl3) δ -104.97 (d, J = 8.2 Hz), -113.01 (d, J = 8.2 Hz). 13C NMR (75 MHz, CDCl3) δ 165.23–153.86 (m), 139.12–137.94 (m), 136.60 (d, J = 3.6 Hz), 126.77, 117.73, 112.25, 108.06 (d, J = 27.1 Hz), 105.72–102.58 (m). HRMS (EI+) m/z, calcd for C8H3N2F2S [M]+: 196.9985, found: 196.9992.
4,6-Dimethoxybenzo[d]thiazole-2-carbonitrile (4z). White powder (0.072 g, 65%), m.p. 140–141 °C. IR (neat) νmax: 2979, 2223 (CN), 1598, 1572, 1476, 1452, 1290, 1218, 1165, 1039, 819, 813, 799 cm−1. 1H NMR (300 MHz, CDCl3) δ 6.92 (d, J = 2.1 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 4.04 (s, 3H), 3.91 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.30, 155.18, 138.88, 138.47, 131.59, 113.28, 99.51, 94.42, 56.47, 56.17. HRMS (EI+) m/z, calcd for C10H9N2O2S [M]+: 221.0385, found: 221.0390.
4-Fluoro-6-methoxybenzo[d]thiazole-2-carbonitrile (4aa). Pale brown solid (0.067 g, 64%), m.p.: 153–154 °C. IR (neat) νmax: 2916, 2847, 2226 (CN), 1615, 1566, 1476, 1443, 1290, 1132, 1027, 858, 826, 572 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.16 (dd, J = 2.3, 0.8 Hz, 1H), 6.96 (dd, J = 11.4, 2.3 Hz, 1H), 3.92 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.72 (d, J = 10.2 Hz), 156.83 (d, J = 261.5 Hz), 139.19 (d, J = 4.2 Hz), 136.77 (d, J = 15.0 Hz), 133.73, 112.82, 104.37 (d, J = 20.3 Hz), 99.35 (d, J = 4.0 Hz), 56.51. 19F NMR (282 MHz, CDCl3) δ −116.73. HRMS (EI+) m/z, calcd for C9H6N2OFS [M]+: 209.0185, found: 209.0193.
5,7-Dimethylbenzo[d]thiazole-2-carbonitrile (4ab). White powder (0.056 g, 59%), m.p. 90–91 °C. IR (neat) νmax: 2921, 2232 (CN), 1556, 1459, 1378, 1289, 1145, 1124, 1037, 872, 689, 611, 563, 481 cm−1.1H NMR (300 MHz, CDCl3) δ 7.82 (dt, J = 1.6, 0.8 Hz, 1H), 7.24 (dt, J = 1.6, 0.8 Hz, 1H), 2.56 (d, J = 0.8 Hz, 3H), 2.51 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 152.74, 138.71, 135.90, 133.39, 131.51, 130.62, 122.43, 113.36, 21.51, 21.30. HRMS (EI+) m/z, calcd for C10H9N2S [M]+: 189.0486, found: 189.0471.
5,7-Dimethoxybenzo[d]thiazole-2-carbonitrile (4ac). White powder (0.072 g, 65%), m.p. 179–180 °C. IR (neat) νmax: 3085, 2979, 2947, 2224 (CN), 1601, 1571, 1407, 1303, 1158, 1125, 9354, 833, 819, 498 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.23 (d, J = 2.0 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 161.80, 154.46, 154.25, 137.37, 117.97, 113.34, 100.19, 98.18, 56.37, 56.09. HRMS (EI+) m/z, calcd for C10H9N2O2S [M]+: 221.0385, found: 221.0394.
5-methyl-7-bromobenzo[d]thiazole-2-carbonitrile and 5-bromo-7-methylbenzo[d]thiazole-2-carbonitrile (4ad’ + 4ad’’) 4ad’: 1H NMR (300 MHz, CDCl3) δ 8.25–8.19 (m, 1H), 7.55 (dd, J = 1.8, 0.9 Hz, 1H), 2.61 (t, J = 0.8 Hz, 3H). 4ad’’: 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 1.4, 0.6 Hz, 1H), 7.60 (dd, J = 1.4, 0.6 Hz, 1H), 2.55 (t, J = 0.6 Hz, 3H).
5-Methoxy-7-bromobenzo[d]thiazole-2-carbonitrile (4ae’). White powder (0.014 g, 11%), m.p. 170–171°C. IR (neat) νmax: 2235 (CN), 1590, 1537, 1464, 1448, 1394, 1274, 1158, 1086, 1024, 983, 841, 722, 633, 480, 423 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 3.91 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.86, 153.01, 137.57, 130.83, 122.42, 113.75, 112.87, 105.85, 56.27. HRMS (EI+) m/z, calcd for C9H5N2OS79Br [M]+: 267.9306, found: 267.9309.
5-Bromo-7-methoxybenzo[d]thiazole-2-carbonitrile (4ae’’). White powder (0.029 g, 24%), m.p. 170–171°C. IR (neat) νmax: 3071, 2931, 2233 (CN), 1554, 1451, 1278, 1121, 972, 863, 836, 565, 385 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 1.5 Hz, 1H), 7.11 (d, J = 1.5 Hz, 1H), 4.03 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 154.33, 154.15, 138.43, 123.91, 122.48, 120.40, 112.77, 111.79, 56.76. HRMS (EI+) m/z, calcd for C9H5N2OS79Br [M]+: 267.9306, found: 267.9304.

4. Conclusions

We have investigated reaction conditions involving palladium and copper to achieve the successful cyclization of cyanothioformamides (3), leading to benzothiazoles 4 substituted in various positions and bearing in position C2 the versatile carbonitrile function. In this process, the presence of 2.0 equiv of an inorganic additive such as KI proved to be essential for a better conversion. The presence of air was also found to be crucial to the reaction, allowing reoxidation of Pd0 at the end of the process. In many cases, the selective C-H functionalization/C-S bond formation reactions were performed in good to very good yields, allowing a wide range of benzothiazole derivatives. In comparison with previous work, this synthetic route produced only one regioisomer, except in the case of unsymmetrical 3,5-disubstituted thioformanilides wherein steric effects due to substituents may influence the reaction outcome. Moreover, this work allowed the formation of an array of polyfunctionalized 2-cyanobenthiazoles, as building blocks for the construction of more complex heterocyclic systems or potent applications in molecular labeling.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27238426/s1: Synthesis of detailed procedures and physicochemical characterization of products N-arylimino-1,2,3-dithiazoles (2) and N-arylcyanothioformamides (3) (Sections S2–S11). 1H NMR and 13C NMR spectra of compounds 4a–z and 4aa-4ag (Sections S12–S47).

Author Contributions

Conceptualization, T.B.; methodology, N.B. and T.B.; investigations, N.B. helped by A.P.-B.; writing—original draft preparation, T.B.; writing—review and editing, T.B., C.F. and N.B.; supervision, C.F. and T.B.; funding acquisition, C.F. and T.B. All authors have read and agreed to the published version of the manuscript.

Funding

This work was partially supported by the European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, and graduate school for research Xl-Chem (ANR-18-EURE-0020 XL CHEM).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We gratefully acknowledge the MESR (Ministère de l’Enseignement Supérieur & de la Recherche, France) for the doctoral fellowships to N.B., T.B. and his co-workers thank the University of Rouen Normandie, INSA Rouen Normandie, CNRS (Centre National de la Recherche Scientifique) and Region Normandie for multiform support.

Conflicts of Interest

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

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 27 08426 g001 550
Figure 1. Synthesis of 2-cyanated benzothiazoles from 5-N-arylimino-4-chloro-1,2,3-dithiazoles and N-arylcyanothioformamides and description of the present work. References involved in these studies: [47,48,51,52,55,57].
Figure 1. Synthesis of 2-cyanated benzothiazoles from 5-N-arylimino-4-chloro-1,2,3-dithiazoles and N-arylcyanothioformamides and description of the present work. References involved in these studies: [47,48,51,52,55,57].
Molecules 27 08426 g001
Molecules 27 08426 sch001 550
Scheme 1. Synthesis of dithiazoles 2 and cyanothioformanilides 3 from anilines 1.
Scheme 1. Synthesis of dithiazoles 2 and cyanothioformanilides 3 from anilines 1.
Molecules 27 08426 sch001
Molecules 27 08426 sch002 550
Scheme 2. Synthesis of 6, 5 and 4-mono-substituted 2-cyanobenzothiazoles (4a-p) from corresponding 4, 3 and 2-mono-substituted anilines (1a-p) (isolated yields).
Scheme 2. Synthesis of 6, 5 and 4-mono-substituted 2-cyanobenzothiazoles (4a-p) from corresponding 4, 3 and 2-mono-substituted anilines (1a-p) (isolated yields).
Molecules 27 08426 sch002
Molecules 27 08426 sch003 550
Scheme 3. Synthesis of 5,6-, 4,5- and 4,6-disubstituted 2-cyanobenzothiazoles (4q-4aa) from corresponding 3,4-, 2,3 and 2,4-disubstituted anilines (1q-1aa) (isolated yields).
Scheme 3. Synthesis of 5,6-, 4,5- and 4,6-disubstituted 2-cyanobenzothiazoles (4q-4aa) from corresponding 3,4-, 2,3 and 2,4-disubstituted anilines (1q-1aa) (isolated yields).
Molecules 27 08426 sch003
Molecules 27 08426 sch004 550
Scheme 4. Synthesis of 5,7- and 4,7-di-substituted 2-cyanobenzothiazoles (4q-4aa) from corresponding 3,5-, and 2,5-di-substituted cyanothioformamides (3ab-3ag) (isolated yields). 1 Yields calculated from 1H-NMR. 2 KI was replaced by LiBr.
Scheme 4. Synthesis of 5,7- and 4,7-di-substituted 2-cyanobenzothiazoles (4q-4aa) from corresponding 3,5-, and 2,5-di-substituted cyanothioformamides (3ab-3ag) (isolated yields). 1 Yields calculated from 1H-NMR. 2 KI was replaced by LiBr.
Molecules 27 08426 sch004
Molecules 27 08426 sch005 550
Scheme 5. Suggested mechanism for synthesis of 2-cyanobenzothiazoles (4) from N-arylcyanothioformamides (3).
Scheme 5. Suggested mechanism for synthesis of 2-cyanobenzothiazoles (4) from N-arylcyanothioformamides (3).
Molecules 27 08426 sch005
Table
Table 1. Preliminary exploration of reaction conditions.
Table 1. Preliminary exploration of reaction conditions.
Molecules 27 08426 i001
EntryPdCl2 (x mol%)Solvent [c] (M)Yield (%) 1
1100.05040
2100.02544
3200.05046
4200.02549 2
1 Isolated yields. 2 51% with TBAI in place of TBAB.
Table
Table 2. Effect of inorganic additives and ambient atmosphere.
Table 2. Effect of inorganic additives and ambient atmosphere.
Molecules 27 08426 i002
EntryAdditiveYield (%) 1EntryAdditiveYield (%) 1
1CsF156KF16
2CsI327LiBr53
3NaI538LiCl33
4KBr669LiI55
5KI70 2,3,4,510none37
1 Isolated yields. 2 23% when performed under inert atmosphere (argon). 3 39% with 3.0 equiv of KI. 4 Replacing KI with a base of K2CO3 or LiOtBu did not provide successful results. 5 Adding a ligand (50 mol%) including phenantroline or L-proline gave 0% and 7% yields of 4a, respectively.
Table
Table 3. Optimization of the palladium and copper sources as well as the solvent.
Table 3. Optimization of the palladium and copper sources as well as the solvent.
Molecules 27 08426 i003
Entry[Pd][Cu]Solvent/Co-SolventYield (%) 1
1PdCl2CuIDMSO/DMF70
2PdBr2CuIDMSO/DMF67
3Pd(OAc)2CuIDMSO/DMF22
4Pd2dba3CuIDMSO/DMF7
5noneCuIDMSO/DMF0
6PdCl2CuBrDMSO/DMF53
7PdCl2CuCl2DMSO/DMF57
8PdCl2Cu(OAc)2DMSO/DMF39
9PdCl2noneDMSO/DMF41
10PdCl2CuIDMSO/NMP18
11PdCl2CuIDMSO/-34
12PdCl2CuIDMF/-14
1 Isolated yields.
Table
Table 4. Optimization of PdCl2 and CuI sources as well as starting molar concentration.
Table 4. Optimization of PdCl2 and CuI sources as well as starting molar concentration.
Molecules 27 08426 i004
EntryPdCl2 (x mol%)CuI (y mol%)[c] MYield (%) 1
120500.02570
220500.05053
320200.02551
410500.02521
510200.02514
1 Isolated yields.
Table
Table 5. Synthesis of dithiazoles 2 and cyanothioformanilides 3 from anilines 1.
Table 5. Synthesis of dithiazoles 2 and cyanothioformanilides 3 from anilines 1.
AnilineRYield of 2 (%) 1Yield of 3 (%) 1AnilineRYield of 2 (%) 1Yield of 3 (%) 1
1a4-Me67 246 61r3,4-diOMe61 871 6
1bH59 241 61s3-Me, 4-Br8463
1c4-F86 347 61t3,4(-OCH2O-)26 955
1d4-Cl82 245 61u3,4(-OCH2CH2O-)65 1071
1e4-Br86 4471v2,3-diMe6479
1f4-OMe48 233 61w2,3-diCl8778 6
1g4-CF37256 61x2-Me, 3-Cl7785
1h4-CN69 5711y2,4-diF94 364 6
1i4-NO28532 61z2,4-diOMe75 575 6
1j4-CO2Et7882 61aa2-F, 4-OMe9275
1k3-OMe74 268 61ab3,5-diMe9177
1l3-NO29081 61ac3,5-diOMe4565
1m3-CO2Et85751ad3-Br, 5-Me6344
1n2-Cl89831ae3-Br, 5-OMe9585
1o2-Br85 280 61af2,5-diMe69 477
1p2-OMe90 7791ag2-Me, 5-iPr76 578
1q3,4-diMe8852----
1 Isolated yield. Compounds described in 2 [48]; 3 [47]; 4 [50]; 5 [64]; 6 [57]; 7 [17]; 8 [65]; 9 [66]; 10 [67].
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Broudic, N.; Pacheco-Benichou, A.; Fruit, C.; Besson, T. Synthesis of 2-Cyanobenzothiazoles via Pd-Catalyzed/Cu-Assisted C-H Functionalization/Intramolecular C-S Bond Formation from N-Arylcyanothioformamides. Molecules 2022, 27, 8426. https://doi.org/10.3390/molecules27238426

AMA Style

Broudic N, Pacheco-Benichou A, Fruit C, Besson T. Synthesis of 2-Cyanobenzothiazoles via Pd-Catalyzed/Cu-Assisted C-H Functionalization/Intramolecular C-S Bond Formation from N-Arylcyanothioformamides. Molecules. 2022; 27(23):8426. https://doi.org/10.3390/molecules27238426

Chicago/Turabian Style

Broudic, Nathan, Alexandra Pacheco-Benichou, Corinne Fruit, and Thierry Besson. 2022. "Synthesis of 2-Cyanobenzothiazoles via Pd-Catalyzed/Cu-Assisted C-H Functionalization/Intramolecular C-S Bond Formation from N-Arylcyanothioformamides" Molecules 27, no. 23: 8426. https://doi.org/10.3390/molecules27238426

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