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Communication

A Novel PIFA/KOH Promoted Approach to Synthesize C2-arylacylated Benzothiazoles as Potential Drug Scaffolds

by
Xiao-Tong Sun
,
Zhi-Gang Hu
,
Zhen Huang
,
Ling-Li Zhou
and
Jian-Quan Weng
*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(3), 726; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030726
Submission received: 30 December 2021 / Revised: 20 January 2022 / Accepted: 21 January 2022 / Published: 22 January 2022
(This article belongs to the Special Issue New Synthetic Methodology for Drug-Like Molecules)
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Abstract

:
To discover an efficient and convenient method to synthesize C2-arylacylated benzothiazoles as potential drug scaffolds, a novel [bis(trifluoroacetoxy)iodo]benzene(PIFA)/KOH synergistically promoted direct ring-opening C2-arylacylation reaction of 2H-benzothiazoles with aryl methyl ketones has been developed. Various substrates were tolerated under optimized conditions affording the C2-arylacylation products in 70–95% yields for 38 examples. A plausible mechanism was also proposed based on a series of controlled experiments.

1. Introduction

Benzothiazole skeletons exist as key building blocks in natural products, drugs and agrochemicals and exhibit potent and diverse biological activities [1,2,3,4]. The benzothiazole scaffold is considered to be one of the most important substructures for drug discovery due to its various biological effects, including anti-cancer, anti-oxidant, anti-inflammatory, anti-microbial, anti-fungal, anti-convulsant, and anti-viral activities [5,6,7,8,9,10,11]. Among them, C2-arylacylated benzothiazole derivatives have attracted considerable attention in recent years due to their great potential as new drug candidates. For instance, as shown in Figure 1, 6-hydroxybenzothiophene ketone A exhibits potential for the treatment of breast cancer, endometriotic tissues, and other diseases by functioning as an inhibitor of 17b-hydroxysteroid dehydrogenase Type 1 (17b-HSD1) [12,13,14]. C2-arylacylated benzothiazole B act as a novel structural class of Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitors with the potential to be developed as anti-inflammatory agents [15]; 2-Benzothiazolyl-phenylmethanone C were found to be potent fatty acid amide hydrolase (FAAH) inhibitors with beneficial effects for disorders such as pain and inflammation [16]. As a potent inhibitor of antiapoptotic Bcl-2 proteins, acylpyrogallol D inhibited growth and induced apoptosis in human breast and prostate cancer cell lines [17]. Keto-benzothiazole E acted as a potent antiproliferative agent for melanoma [18], while F can potentially treat schizophrenia by inhibiting PDE10A [19].
Given their extensive potential for therapeutic use, the development of efficient synthetic strategies for C2-arylacylated benzothiazoles is an attractive research topic. Up to now, several methods have been investigated for the synthesis of C2-arylacylated benzothiazoles, including cyclization with or without the sulfuration of ortho-substituted anilines [20,21,22,23] and sp2 C–H bond functionalization of 2H-benzothiazoles. From the perspective of synthetic simplicity and atom economy, the direct C2-functionalization method is relatively advantageous. Great efforts have been devoted to preparing C2-arylacylated benzothiazoles by the direct C2-functionalization of 2H-benzothiazoles with aryl methyl ketones [24,25,26,27], phenylglyoxal [28], α-oxocarboxylic acids [29,30], benzoic acid [31], and benzoyl chloride [32]. In particular, the direct C2-arylacylation of 2H-benzothiazoles with aryl methyl ketones has generated great interest due to many “readily available” and “inexpensive” aryl methyl ketone analogs. In 2013, Deng and co-workers [24] reported the C2-arylacylation of 2H-benzothiazoles using O2 as the oxidant in the presence of FeCl3·6H2O/P(Cy)3HBF4 at 120 °C (Figure 2a). In 2014, a FeCl3·6H2O-catalyzed C2-arylacylated reaction of 2H-benzothiazoles using K2S2O8 as an oxidant was reported by Yu and co-workers [25] (Figure 2b). The same year, Song and co-workers [26] reported the CuI-catalyzed C2-arylacylation of 2H-benzothiazoles under a nitrogen atmosphere (Figure 2c). In 2020, Ablajan and co-workers [27] developed a protocol for the C2-arylacylation of 2H-benzothiazoles in the presence of I2 and TBHP (Figure 2d). Despite these notable advances, they still suffered from certain limitations such as relatively high reaction temperature, the transitional metal catalysts and inevitable metal residues, the use of the strongly corrosive additive HBF4, or the expensive ligand P(Cy)3HBF4. In addition, flammable and explosive organic peroxides were used as oxidizing reagents.
In recent years, PIFA has received significant attention as a mild, low-toxic, and selective reagent in organic synthesis, which can also be used as an effective alternative to toxic, heavy metal-based oxidants, and expensive organometallic catalysts [33,34,35]. In line with our continuous efforts to extend the C2-functionalization methods for 2H-benzothiazoles [36,37,38,39,40], herein we report a novel, convenient, and efficient PIFA/KOH method which synergistically promotes the C2-arylacylation of 2H-benzothiazoles with aryl methyl ketones, affording a wide variety of 2-arylacylated products with good yields. Our process also has the advantages of mild reaction conditions and being transitional metal-free.

2. Results and Discussion

2.1. Optimization of Reaction Conditions

Initially, we chose 2H-benzothiazole (1a) and acetophenone (2a) as the model substrates to investigate the reaction conditions. The results are outlined in Table 1. Our examination of a series of common solvents demonstrated that the reactions led to the desired arylacylated product with a 7% yield in DMSO, while no product was produced in MeCN, DMF, and H2O (Table 1, entries 1–4). To our delight, the reaction efficiency was greatly improved when DMSO was mixed with H2O. The experimental results indicated that the product yield reached 60% in the mixture of DMSO and H2O with a volume ratio of 3:1 (Table 1, entries 5–8). In addition, the screening of different bases showed that KOH provided the greatest yield (75%) of the desired product (Table 1, entries 7 and 9–11). From the results in entries 11–14, it can be deduced that the base is necessary, with the optimal amount of KOH being one equivalent of 2a. Furthermore, we changed the amount of PIFA, but poorer yields were obtained in all cases (Table 1, entries 16–18), and no product was observed in the absence of PIFA (Table 1, entry 15). Further investigation indicated that the temperature is very important for this transformation; the yield declined when the reaction temperature was decreased to 75 °C or increased to 95 °C (Table 1, entries 19–20). When the reaction time increased from 8 h to 10 h, the yield of 3aa was increased to 86%, but no significant improvement was observed when the reaction time was increased to 12 h (Table 1, entries 21–22). Thus, the optimal reaction conditions involved PIFA (2 eq.) and KOH (1 eq.) in DMSO/H2O (3:1, v/v) at 85 °C for 10 h (Table 1, entry 21).
Notably, the procedure was applicable to a 10 mmol scale (1.20 g), and the product 3aa was isolated in 79% (1.89 g) yield under the optimized reaction conditions (Figure 3).

2.2. Expansion of Substrate Scope

With these optimized reaction conditions in mind, the scope of aryl methyl ketones (2) was first explored for the arylacylation of 2H-benzothiazole (1a). As shown in Figure 4, the reactions with aryl methyl ketones bearing a methyl group at ortho-, meta-, and para- positions gave the corresponding arylacylated products in 80–85% yields (Figure 4a, 3ab-3ad). The halogenated acetophenones (2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br,3-Br, 4-Br, 2-I, 3-I, and 4-I) produced corresponding products in 70–88% yield (Figure 4a, 3ae-3ap). In addition, 4-butylacetophenone, 4-methoxyacetophenone, 4-phenylacetophenone, and 2-acetonaphthalene all formed corresponding arylacylated products in high yields of 86–95% (Figure 4a, 3aq-3at). The above results demonstrated that a wide variety of aryl methyl ketones bearing either electron-donating or electron-withdrawing groups were well tolerated in this reaction.
Our scope was also extended to substituted 2H-benzothiazoles and substituted aryl methyl ketones to investigate the utility and limits of the reaction (Figure 4b). To our delight, the reactions of 6-methoxybenzothiazole and 5-chlorobenzothiazole with aryl methyl ketones containing either electron-donating methyl and n-butyl groups or electron-withdrawing halogens; including fluoro, chloro, bromo, or iodo moieties or in addition to phenyl groups were well tolerated. These reactions all afforded corresponding arylacylated products in 72–92% yields (Figure 4b, 3ba-bp). Meanwhile, 6-nitrobenzothiazole and 6-benzothiazolecarbonitrile were also tolerated by the reaction conditions, producing corresponding products 3bq and 3br in 87% and 80% yield, respectively. The results demonstrated that the 2H-benzothiazoles bearing electron-withdrawing or electron-donating groups were compatible with a variety of aryl methyl ketones. Unfortunately, the desired reaction did not occur between 6-aminobenzothiazole and acetophenone (3bs), presumably because the amino group is readily oxidizable.

2.3. Mechanism Study

In addition, a series of controlled experiments were used to explore the reaction mechanism as follows: (A) Two equivalents of the radical trap 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) were added to the mixture under optimal reaction conditions (Figure 5a). TEMPO, a known radical scavenger, will intercept the free radicals generated by the reaction, thus inhibiting the progress of the reaction [27]. The results indicated that the reaction was almost completely inhibited by TEMPO, with only a trace amount of 3aa being detected. (B) The reaction mechanism behind the ring-opening of the 2H-benzothiazole was explored. The 2H-benzothiazole was transformed into 2-aminothiophenol (1b) in 83% yield under standard conditions (Figure 5b). (C) The reaction between 2-aminothiophenol (1b) and acetophenone (2a), under optimized reaction conditions, formed the target product (3aa) in 87% yield, which was close to that of the reaction between 2H-benzothiazole and acetophenone (86%, Figure 4, 3aa). This confirmed that the transformation might proceed via a ring-opening pathway. (D) The reaction between 2H-benzothiazole (1a) and 2,2-dihydroxy-1-phenylethan-1-one (2b) afforded 3aa in 92% yield (Figure 5d). This result demonstrated that acetophenone (2a) was oxidized to phenylglyoxal (2b). (E) The reaction of 2-aminothiophenol (1b) with 2,2-dihydroxy-1-phenylethan-1-one (2b) afforded the desired product 3aa in 94% yield, suggesting that 2-aminothiophenol (1b) was the intermediate product (Figure 5e).
Based on the above experimental results and related reports [24,25,26,27], a plausible mechanism was proposed in Figure 6. Initially, acetophenone (2a) is converted to A in the presence of PIFA, which is similar to the I2 promoted sp3 C-H functionalization [41]. Subsequently, A was further oxidized to phenylglyoxal (B) in the DMSO [28]. In the meantime, the ringopening of 2H-benzothiazole (1a) under KOH produced 2-aminothiophenol (1b) [42]. The condensation of 1b with B formed an imine intermediate C [20,21,22,23], which could generate D through intramolecular cyclization [43]. Finally, the oxidative dehydrogenation of D furnished the target product 3aa through the elimination of CF3COOH and PhI. The presence of the latter compound was detected in the reaction solution by GC-MS [44,45].

3. Conclusions

In summary, we have developed a novel PIFA/KOH synergistically promoted C2-arylacylation of 2H-benzothiazoles using aryl methyl ketones as carbonyl sources. This arylacylation reaction tolerates a wide range of functional groups affording 38 examples of the C2-arylacylated products in 70–95% yield. This protocol provided an efficient and convenient method to synthesize C2-arylacylated benzothiazoles as potential drug scaffolds and complemented the existing approaches for the C2-arylacylation of aromatic rings.

4. Materials and Methods

4.1. General Information

All reactions were carried out under ambient atmosphere conditions in dried glassware. The reaction progress was monitored by TLC using silica gel GF254, and spots were visualized by exposure to UV light (254 nm). Melting points were determined using an X-4 apparatus without correction. NMR spectra were performed on a Bruker ADVANCE III instrument (500 MHz for 1H-NMR and 125 MHz for 13C-NMR) using TMS as an internal standard and CDCl3 or DMSO-d6 as the solvent. The high-resolution mass spectra (HRMS) were determined using a Shimadzu LCMS-IT-TOF mass spectrometer equipped with an electrospray ionization (ESI) source.

4.2. Synthesis

A mixture of 2H-benzothiazole 1 (0.45 mmol), aryl methyl ketone 2 (0.30 mmol), KOH (1 equiv., 0.30 mmol), and PIFA (2 equiv., 0.60 mmol) was heated at 85 °C in DMSO/H2O (v/v, 3/1, 2 mL) for 10 h. After cooling to room temperature, the reaction mixture was diluted with H2O (30 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 20:1 to 8:1) to give products 3aa-3bs.
Benzo[d]thiazol-2-yl(phenyl)methanone (3aa): Yellow solid, yield 86% (61 mg); m.p.: 98–99 °C; 1H NMR (500 MHz, CDCl3) δ 8.58 (dd, J = 8.0, 1.0 Hz, 2H), 8.27 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 7.0 Hz, 1H), 7.73–7.65 (m, 1H), 7.64–7.54 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 185.40, 167.17, 153.94, 137.06, 135.03, 133.91, 131.31, 128.53, 127.64, 126.95, 125.77, 122.19. These spectroscopic data correspond to the reported data in reference [27].
Benzo[d]thiazol-2-yl(o-tolyl)methanone (3ab): Yellow solid; yield 85% (64 mg); m.p.: 110–112 °C; 1H NMR (500 MHz, CDCl3) δ 8.21 (dd, J = 9.0, 1.5 Hz, 1H), 8.03 (td, J = 7.5, 1.0 Hz, 2H), 7.60–7.54 (m, 2H), 7.52–7.48 (m, 1H), 7.37 (t, J = 7.5 Hz, 2H), 2.55 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.27, 167.61, 153.86, 139.11, 137.2, 135.25, 132.03, 131.58, 131.37, 127.69, 126.95, 125.86, 125.35, 122.26, 20.68. These spectroscopic data correspond to the reported data in reference [27].
Benzo[d]thiazol-2-yl(m-tolyl)methanone (3ac): Yellow solid; yield 83% (63 mg); m.p.: 72–74 °C; 1H NMR (500 MHz, CDCl3) δ 8.40 (d, J = 7.5 Hz, 1H), 8.30 (s, 1H), 8.29–8.26 (m, 1H), 8.05–8.03 (m, 1H), 7.63–7.57 (m, 2H), 7.51–7.45 (m, 2H), 2.50 (s, 3H); 13C NMR (125 MHz, CDCl3) 185.69, 167.29, 153.94, 138.35, 137.06, 135.07, 134.76, 131.50, 128.69, 128.43, 127.59, 126.91, 125.78, 122.19, 21.47. These spectroscopic data correspond to the reported data in reference [27].
Benzo[d]thiazol-2-yl(p-tolyl)methanone (3ad): Yellow solid; yield 80% (61 mg); m.p.: 96–98 °C; 1H NMR (500 MHz, CDCl3) δ 8.50 (d, J = 8.5 Hz, 1H), 8.31–8.14 (m, 1H), 8.11–7.92 (m, 1H), 7.58 (dtd, J = 21.0, 7.0, 1.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 1H), 2.49 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 184.94, 153.94, 153.94, 137.01, 132.47, 131.44, 129.28, 127.49, 126.85, 125.69, 122.16, 21.85. These spectroscopic data correspond to the reported data in reference [27].
Benzo[d]thiazol-2-yl(2-fluorophenyl)methanone (3ae): Yellow solid; yield 77% (59 mg); m.p.: 81–83 °C; 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 7.3 Hz, 1H), 8.06–8.01 (m, 2H), 7.64–7.55 (m, 3H), 7.34 (t, J = 7.9 Hz, 1H), 7.25 (dd, J = 17.7, 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 185.33, 166.21, 161.24 (d, J = 255.0 Hz), 153.72, 137.29, 134.41 (d, J = 8.8 Hz), 131.91, 127.86, 127.04, 125.86, 124.89 (d, J = 11.3 Hz), 124.00 (d, J = 3.75 Hz), 122.29, 116.69 (d, J = 21.0 Hz). These spectroscopic data correspond to the reported data in reference [26].
Benzo[d]thiazol-2-yl(3-fluorophenyl)methanone (3af): Yellow solid; yield 81% (62 mg); m.p.: 78–80 °C; 1H NMR (500 MHz, CDCl3) δ 8.41 (d, J = 8.0 Hz, 1H), 8.35 (ddd, J = 9.5, 2.5, 1.5 Hz, 1H), 8.28 (d, J = 7.0 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.64–7.55 (m, 3H), 7.39 (tdd, J = 8.0, 2.5, 1.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.97, 166.62, 153.90, 137.13, 130.16 (d, J = 7.5 Hz), 127.89, 127.11, 125.90, 122.23, 120.95 (d, J = 21.3 Hz), 118.17 (d, J = 23.8 Hz). These spectroscopic data correspond to the reported data in reference [26].
Benzo[d]thiazol-2-yl(4-fluorophenyl)methanone (3ag): Yellow solid; yield 85% (65.6 mg); m.p.: 100–102 °C; 1H NMR (500 MHz, CDCl3) δ 8.70 (dd, J = 8.5, 5.5 Hz, 2H), 8.29–8.24 (m, 1H), 8.06–8.02 (m, 1H), 7.60 (dtd, J = 15.5, 7.5, 1.5 Hz, 2H), 7.26 (t, J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 183.56, 167.06, 166.42 (d, J = 256.0 Hz), 153.87, 137.03, 134.19 (d, J = 8.8 Hz), 131.32 (d, J = 2.5 Hz), 127.70, 126.99, 125.71, 122.18, 115.73 (d, J = 22.5 Hz). These spectroscopic data correspond to the reported data in reference [26].
Benzo[d]thiazol-2-yl(2-chlorophenyl)methanone (3ah): Yellow solid; yield 75% (61 mg); m.p.: 92–93 °C; 1H NMR (500 MHz, CDCl3) δ 8.21–8.17 (m, 1H), 8.06–8.01 (m, 1H), 7.80–7.76 (m, 1H), 7.62–7.49 (m, 6H), 7.45 (ddd, J = 7.5, 6.0, 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 187.61, 165.95, 153.76, 137.45, 136.07, 132.63, 132.36, 130.79, 130.55, 127.97, 127.07, 126.49, 125.97, 122.33. These spectroscopic data correspond to the reported data in reference [26].
Benzo[d]thiazol-2-yl(3-chlorophenyl)methanone (3ai): Yellow solid; yield 79% (64 mg); m.p.: 128–129 °C; 1H NMR (500 MHz, CDCl3) δ 8.58 (t, J = 2.0 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.67–7.51 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 184.05, 166.48, 153.86, 137.11, 136.50, 134.73, 133.80, 131.19, 129.82, 129.45, 127.90, 127.11, 125.91, 122.22. These spectroscopic data correspond to the reported data in reference [27].
Benzo[d]thiazol-2-yl(4-chlorophenyl)methanone (3aj): Yellow solid; yield 77% (60 mg); m.p.: 99–101 °C; 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J = 8.5 Hz, 2H), 8.26 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.64–7.54 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 184.06, 166.86, 153.89, 140.67, 137.10, 133.33, 132.76, 128.91, 127.82, 127.08, 125.80, 122.23. These spectroscopic data correspond to the reported data in reference [26].
Benzo[d]thiazol-2-yl(2-bromophenyl)methanone (3ak): Yellow solid; yield 80% (76 mg); m.p.: 103–105 °C; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J = 9.5 Hz, 1H), 8.04 (d, J = 9.5 Hz, 1H), 7.77–7.70 (m, 3H), 7.60–7.55 (m, 2H), 7.50 (td, J = 7.5, 1.0 Hz, 1H), 7.44 (td, J = 8.0, 2.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 188.31, 165.67, 153.76, 138.09, 137.50, 133.70, 132.37, 130.71, 128.00, 127.07, 125.99, 122.34, 120.64. These spectroscopic data correspond to the reported data in reference [26].
Benzo[d]thiazol-2-yl(3-bromophenyl)methanone (3al): Yellow solid; yield 86% (82 mg); m.p.: 98–100 °C; 1H NMR (500 MHz, CDCl3) δ 8.72 (t, J = 2.0 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.64–7.57 (m, 2H), 7.47 (t, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.99, 136.70, 134.05, 129.99, 127.91, 127.11, 125.93, 122.68, 122.22. These spectroscopic data correspond to the reported data in reference [27].
Benzo[d]thiazol-2-yl(4-bromophenyl)methanone (3am): Yellow solid; yield 88% (84 mg); m.p.: 92–94 °C; 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 8.5 Hz, 2H), 8.25 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.63–7.56 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 184.27, 166.80, 153.88, 137.10, 133.74, 132.80, 131.89, 129.53, 127.83, 127.08, 125.81, 122.23. These spectroscopic data correspond to the reported data in reference [27].
Benzo[d]thiazol-2-yl(2-iodophenyl)methanone (3an): Yellow solid; yield 73% (79 mg); m.p.: 121–123 °C; 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.0 Hz, 1H), 8.08–8.04 (m, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.74 (dd, J = 8.0, 2.0 Hz, 1H), 7.60–7.55 (m, 1H), 7.52–7.44 (m, 2H), 7.19 (td, J = 8.0, 1.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 167.98, 140.66, 136.18, 131.52, 131.30, 128.25, 126.40, 125.59, 123.77, 121.57, 96.35. ESI-HRMS calcd C14H8INOS [M + H]+ 365.9450; found, 365.9469.
Benzo[d]thiazol-2-yl(3-iodophenyl)methanone (3ao): Yellow solid; yield 75% (82 mg); m.p.: 105–107 °C; 1H NMR (500 MHz, CDCl3) δ 8.87 (t, J = 1.5 Hz, 1H), 8.59 (dt, J = 7.5, 1.5 Hz, 1H), 8.29–8.26 (m, 1H), 8.04–7.99 (m, 2H), 7.63–7.57 (m, 2H), 7.32 (t, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.82, 166.36, 153.82, 142.53, 139.79, 137.08, 136.69, 130.50, 130.12, 127.87, 127.07, 125.90, 122.19, 94.02. ESI-HRMS calcd C14H8INOS [M + H]+ 365.9450; found, 365.9468.
Benzo[d]thiazol-2-yl(4-iodophenyl)methanone (3ap): Yellow solid; yield 70% (76 mg); m.p.: 113–115 °C; 1H NMR (500 MHz, CDCl3) δ 8.33–8.29 (m, 2H), 8.27–8.23 (m, 1H), 8.06–8.01 (m, 1H), 7.97–7.93 (m, 2H), 7.64–7.56 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 184.58, 166.73, 153.83, 137.87, 137.07, 134.23, 132.56, 127.80, 127.05, 125.78, 122.20, 102.57. These spectroscopic data correspond to the reported data in reference [46].
Benzo[d]thiazol-2-yl(4-butylphenyl)methanone (3aq): Yellow liquid; yield 95% (84 mg); 1H NMR (500 MHz, CDCl3) δ 8.52 (d, J = 8.0 Hz, 2H), 8.31–8.19 (m, 1H), 8.07–7.91 (m, 1H), 7.62–7.52 (m, 2H), 7.38 (d, J = 8.4 Hz, 2H), 2.78–2.70 (m, 2H), 1.71–1.63 (m, 2H), 1.46–1.36 (m, 2H), 1.02–0.91 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 184.88, 167.51, 153.91, 149.88, 136.98, 132.60, 131.45, 128.64, 127.51, 126.82, 125.66, 122.13, 35.87, 33.15, 22.35, 13.91. ESI-HRMS calcd C18H8NOS [M + H]+ 296.1109; found, 296.1109.
Benzo[d]thiazol-2-yl(4-methoxyphenyl)methanone (3ar): Yellow solid; yield 91% (73 mg); m.p.: 126–128 °C; 1H NMR (500 MHz, CDCl3) δ 8.69–8.63 (m, 2H), 8.28–8.22 (m, 1H), 7.95–7.82 (m, 1H), 7.65–7.51 (m, 2H), 7.04–6.98 (m, 2H), 3.90 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.41, 167.91, 164.42, 153.91, 136.90, 133.85, 127.80, 127.35, 126.77, 125.53, 122.11, 113.89, 55.55. These spectroscopic data correspond to the reported data in reference [26].
[1,1′-Biphenyl]-4-yl(benzo[d]thiazol-2-yl)methanone (3as): White solid; yield 86% (81 mg); m.p.: 100–102 °C; 1H NMR (500 MHz, CDCl3) δ 8.68 (d, J = 8.5 Hz, 2H), 8.29 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 7.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 7.0 Hz, 2H), 7.63–7.57 (m, 2H), 7.55–7.49 (m, 2H), 7.47–7.42 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 184.78, 167.35, 153.93, 146.56, 139.90, 137.04, 133.71, 131.89, 128.99, 128.38, 127.60, 127.37, 127.17, 126.93, 125.73, 122.18. These spectroscopic data correspond to the reported data in reference [46].
Benzo[d]thiazol-2-yl(naphthalen-2-yl)methanone (3at): Yellow solid; yield 88% (76 mg); m.p.: 145–147 °C; 1H NMR (500 MHz, CDCl3) δ 9.36 (s, 1H), 8.46 (d, J = 9.0 Hz, 1H), 8.32 (d, J = 7.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.70–7.58 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 185.07, 167.41, 153.96, 137.04, 135.98, 134.36, 132.48, 132.24, 130.24, 129.02, 128.34, 127.78, 127.58, 126.91, 126.73, 125.83, 125.76, 122.18. These spectroscopic data correspond to the reported data in reference [26].
(6-Methoxybenzo[d]thiazol-2-yl)(phenyl)methanone (3ba): Yellow solid; yield 81% (65 mg); m.p.: 138–140 °C; 1H NMR (500 MHz, CDCl3) δ 8.56 (dd, J = 8.0, 1.0 Hz, 2H), 8.12 (d, J = 9.0 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 8.0 Hz, 2H), 7.43 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 9.0, 2.5 Hz, 1H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 185.21, 164.70, 159.84, 148.61, 139.16, 135.26, 133.68, 131.20, 128.46, 126.51, 117.63, 103.49, 55.89. These spectroscopic data correspond to the reported data in reference [36].
(6-Methoxybenzo[d]thiazol-2-yl)(p-tolyl)methanone (3bb): Yellow solid; yield 80% (68 mg); m.p.: 153–155 °C; 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J = 8.0 Hz, 2H), 8.11 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.19 (dd, J = 9.5, 3.0 Hz, 1H), 3.94 (s, 3H), 2.48 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 184.72, 164.98, 159.67, 148.54, 144.71, 139.03, 132.60, 131.29, 129.19, 126.39, 117.50, 103.40, 55.85, 21.83. These spectroscopic data correspond to the reported data in reference [36].
(4-Fluorophenyl)(6-methoxybenzo[d]thiazol-2-yl)methanone (3bc): Yellow solid; yield 75% (63 mg); m.p.: 167−169 °C; 1H NMR (500 MHz, CDCl3) δ 8.67 (dd, J = 8.5, 5.5 Hz, 2H), 8.11 (d, J = 9.5 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.27–7.20 (m, 3H), 3.94 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.35, 167.27, 165.23, 164.50, 159.84, 148.48, 139.10, 134.02 (d, J = 8.8 Hz), 126.43, 117.71, 115.64 (d, J = 22.5 Hz), 103.41, 55.89. These spectroscopic data correspond to the reported data in reference [36].
(4-Chlorophenyl)(6-methoxybenzo[d]thiazol-2-yl)methanone (3bd): Yellow solid; yield 76% (69 mg); m.p.: 195−197 °C; 1H NMR (500 MHz, CDCl3) δ 88.58–8.53 (m, 2H), 8.12 (d, J = 9.0 Hz, 1H), 7.56–7.53 (m, 2H), 7.43 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 9.0, 2.5 Hz, 1H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 181.31, 164.28, 159.91, 148.48, 140.82, 140.34, 133.29, 132.60, 128.79, 126.50, 117.79, 103.39, 55.88. These spectroscopic data correspond to the reported data in reference [36].
(4-Bromophenyl)(6-methoxybenzo[d]thiazol-2-yl)methanone (3be): Yellow solid; yield 90% (93 mg); m.p.:184–186 °C; 1H NMR (500 MHz, CDCl3) δ 8.09–8.04 (m, 2H), 7.97 (d, J = 9.0 Hz, 1H), 7.52–7.46 (m, 3H), 7.37 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 9.0, 2.5 Hz, 1H), 3.91 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 181.47, 164.14, 159.94, 148.61, 139.22, 132.68, 131.79, 128.60, 126.52, 117.81, 103.39, 55.88. These spectroscopic data correspond to the reported data in reference [27].
(4-Iodophenyl)(6-methoxybenzo[d]thiazol-2-yl)methanone (3bf): Yellow solid; yield 72% (85 mg); m.p.: 152–153 °C; 1H NMR (500 MHz, CDCl3) δ 8.31–8.26 (m, 2H), 8.11 (d, J = 9.0 Hz, 1H), 7.96–7.93 (m, 2H), 7.43 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 9.0, 2.5 Hz, 1H), 3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 184.38, 163.07, 159.92, 148.62, 145.50, 144.12, 142.39, 137.79, 132.47, 126.52, 117.80, 103.39, 99.99, 55.88. ESI-HRMS calcd C15H10INO2S [M + H]+ 359.9555; found, 359.9576.
(4-Butylphenyl)(6-methoxybenzo[d]thiazol-2-yl)methanone (3bg): Yellow solid; yield 92% (90 mg); m.p.: 100–102 °C; 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 8.0 Hz, 2H), 8.11 (d, J = 9.5 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.21–7.17 (m, 1H), 3.93 (s, 3H), 2.74–2.71 (m, 2H), 1.69–1.65 (m, 2H), 1.43–1.38 (m, 2H), 0.98–0.94 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 184.71, 165.02, 159.67, 149.60, 139.02, 132.77, 131.32, 129.07, 128.57, 126.37, 117.48, 103.42, 55.83, 35.85, 33.17, 22.34, 13.90. ESI-HRMS calcd C19H20NO2S [M + H]+ 326.1215; found, 326.1220.
(6-Methoxybenzo[d]thiazol-2-yl)(4-methoxyphenyl)methanone (3bh): Yellow solid; yield 86% (77 mg); m.p.: 147–149 °C; 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J = 9.0 Hz, 2H), 8.11 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 3.94 (s, 6H).; 13C NMR (125 MHz, CDCl3) δ 183.26, 165.43, 164.23, 159.59, 148.55, 138.92, 133.70, 127.99, 126.25, 117.39, 113.82, 103.44, 55.84, 55.53. These spectroscopic data correspond to the reported data in reference [27].
(6-Methoxybenzo[d]thiazol-2-yl)(4-nitrophenyl)methanone (3bi): Yellow solid; yield 75% (71 mg); m.p.: 152–153 °C; 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J = 9.0 Hz, 2H), 8.40 (d, J = 9.0 Hz, 2H), 8.13 (d, J = 9.5 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 3.96 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.58, 163.29, 160.30, 148.69, 139.35, 137.18, 137.05, 132.16, 127.81, 126.73, 123.42, 116.60, 103.40, 55.86. These spectroscopic data correspond to the reported data in reference [47].
(5-Chlorobenzo[d]thiazol-2-yl)(phenyl)methanone (3bj): Yellow solid; yield 84% (68 mg); m.p. = 133–135 °C; 1H NMR (500 MHz, CDCl3) δ 8.59–8.55 (m, 2H), 8.26 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.60–7.53 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 184.94, 168.98, 154.66, 135.26, 134.72, 134.14, 133.06, 131.33, 128.59, 128.26, 125.28, 122.98. These spectroscopic data correspond to the reported data in reference [27].
(5-Chlorobenzo[d]thiazol-2-yl)(p-tolyl)methanone (3bk): Yellow solid; yield 76% (65 mg); m.p.: 92–93 °C; 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J = 8.5 Hz, 2H), 8.22 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.5, 1.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 2.48 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 184.40, 169.32, 154.64, 145.28, 135.19, 132.93, 132.14, 131.44, 129.31, 128.07, 125.18, 122.91, 21.84. These spectroscopic data correspond to the reported data in reference [27].
(5-Chlorobenzo[d]thiazol-2-yl)(4-fluorophenyl)methanone (3bl): Yellow solid; yield 73% (63 mg); m.p.: 142–144 °C;1H NMR (500 MHz, CDCl3) δ 8.75–8.62 (m, 2H), 8.25 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 8.5, 2.0 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 183.15, 168.89, 165.55, 154.60, 135.24, 134.25 (d, J = 8.8 Hz), 133.15, 128.35, 125.25, 122.99, 115.85 (d, J = 22.5 Hz). These spectroscopic data correspond to the reported data in reference [48].
(5-Chlorobenzo[d]thiazol-2-yl)(4-chlorophenyl)methanone (3bm): Yellow solid; yield 78% (72 mg); m.p.: 185–187 °C; 1H NMR (500 MHz, CDCl3) δ 8.60–8.53 (m, 3H), 8.25 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.57–7.54 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 183.61, 168.66, 154.60, 140.95, 135.29, 133.21, 133.00, 132.76, 128.97, 128.44, 125.31, 123.01. These spectroscopic data correspond to the reported data in reference [26].
(4-Bromophenyl)(5-chlorobenzo[d]thiazol-2-yl)methanone (3bn): Yellow solid; yield 80% (84 mg); m.p.: 184–186 °C; 1H NMR (500 MHz, CDCl3) δ 8.51–8.44 (m, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 9.0 Hz, 0H), 7.74–7.71 (m, 1H), 7.55 (dd, J = 8.5, 2.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.83, 168.60, 154.59, 135.29, 133.41, 133.22, 132.79, 131.96, 129.83, 128.45, 125.31, 123.00. These spectroscopic data correspond to the reported data in reference [27].
(5-Chlorobenzo[d]thiazol-2-yl)(4-iodophenyl)methanone (3bo): Yellow solid; yield 73% (87 mg); m.p.: 182–184 °C; 1H NMR (500 MHz, CDCl3) δ 8.32–8.30 (m, 2H), 8.25 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 4.5 Hz, 2H), 7.55 (dd, J = 8.5, 2.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 183.45, 169.19, 154.55, 135.26, 133.91, 133.17, 132.71, 131.90, 130.93, 128.42, 125.28, 122.99. ESI-HRMS calcd C14H8ClINOS [M + H]+ 399.9060; found, 399.9080.
[1,1′-Biphenyl]-4-yl(5-chlorobenzo[d]thiazol-2-yl)methanone (3bp): Yellow solid; yield 78% (81 mg); m.p.: 159–161 °C; 1H NMR (500 MHz, CDCl3) δ 8.68–8.63 (m, 2H), 8.27 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.81–7.78 (m, 2H), 7.72–7.68 (m, 2H), 7.55–7.50 (m, 3H), 7.47–7.42 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 184.26, 169.17, 154.64, 146.77, 139.77, 135.23, 133.35, 133.02, 131.91, 129.01, 128.46, 128.19, 127.36, 127.19, 125.23, 122.95. ESI-HRMS calcd C20H13ClNOS [M + H]+ 350.0406; found, 350.0410.
(6-Nitrobenzo[d]thiazol-2-yl)(phenyl)methanone (3bq): Yellow solid; yield 87% (74 mg); m.p.: 159–161 °C; 1H NMR (500 MHz, CDCl3) δ 8.98 (d, J = 2.0 Hz, 1H), 8.61 (dd, J = 8.0, 0.5 Hz, 2H), 8.47 (dd, J = 9.0, 2.5 Hz, 1H), 8.39 (d, J = 9.0 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.61 (t, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 191.14, 172.44, 157.19, 146.61, 137.14, 134.59, 134.26, 131.41, 128.75, 126.24, 122.08, 118.86. These spectroscopic data correspond to the reported data in reference [36].
2-Benzoylbenzo[d]thiazole-6-carbonitrile (3br): Yellow solid; yield 80% (63 mg); m.p.: 140–142 °C; 1H NMR (500 MHz, CDCl3) δ 8.59 (d, J = 7.0 Hz, 2H), 8.40 (d, J = 1.0 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 8.5, 1.5 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 171.14, 155.94, 134.51, 134.34, 131.38, 129.67, 128.72, 127.26, 126.54, 118.30, 111.20. These spectroscopic data correspond to the reported data in reference [36].

Supplementary Materials

The following are available online.

Author Contributions

Methodology, X.-T.S. and J.-Q.W.; validation, Z.H. and L.-L.Z.; data curation, X.-T.S. and Z.-G.H.; writing—original draft, X.-T.S.; writing—review and editing, J.-Q.W.; supervision, J.-Q.W.; project administration, J.-Q.W.; funding acquisition, J.-Q.W. All authors have read and agreed to the published version of the manuscript.

Funding

This research was financially supported by the Key Research and Development Program of Zhejiang Province (Grant No. 2022C03016) and the Zhejiang Provincial Natural Science Foundation of China (Grant No. LY17C140003).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study is available in the article or supporting information.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

References

  1. Blunt, C.E.; Nawrat, C.C.; LeBozec, L.; Liutkus, M.; Liu, Y.; Lewis, W.; Moody, C.J. Oxidative routes to the heterocyclic cores of benzothiazole natural products. Synlett 2016, 27, 37–40. [Google Scholar]
  2. Sumit; Kumar, A.; Mishra, A.K. Advancement in pharmacological activities of benzothiazole and its derivatives: An up to date review. Mini-Rev. Med. Chem. 2021, 21, 314–335. [Google Scholar]
  3. Ballari, M.S.; Cano, N.H.; Wunderlin, D.A.; Feresin, G.E.; Santiago, A.N. One-pot sequential synthesis and antifungal activity of 2-(benzylsulfonyl)benzothiazole derivatives. RSC Adv. 2019, 9, 29405–29413. [Google Scholar] [CrossRef] [Green Version]
  4. Bhat, M.; Belagali, S.L. Structural activity relationship and importance of benzothiazole derivatives in medicinal chemistry: A comprehensive review. Mini-Rev. Org. Chem. 2020, 17, 323–350. [Google Scholar] [CrossRef]
  5. Dhumal, S.T.; Deshmukh, A.R.; Kharat, K.R.; Sathe, B.R.; Chavan, S.S.; Mane, R.A. Copper fluorapatite assisted synthesis of new 1,2,3-triazoles bearing a benzothiazolyl moiety and their antibacterial and anticancer activities. New J. Chem. 2019, 43, 7663–7673. [Google Scholar] [CrossRef]
  6. El-Mekabaty, A.; Sofan, M.A.; Hasel, A.M.; Said, S.B. Concise synthesis of some new benzothiazole-based heterocycles as probable anticancer and antioxidant agents. ChemistrySelect 2021, 6, 2569–2575. [Google Scholar] [CrossRef]
  7. Hori, N.; Tsukamoto, G.; Imamura, A.; Ohashi, M.; Saito, T.; Yoshino, K. Novel disease-modifying antirheumatic drugs.1. synthesis and antiarthritic activity of 2-(4-methylphenyl)benzothiazoles. Chem. Pharm. Bull. 1992, 40, 2387–2390. [Google Scholar] [CrossRef] [Green Version]
  8. Haroun, M.; Tratrat, C.; Petrou, A.; Geronikaki, A.; Ivanov, M.; Ciric, A.; Sokovic, M. 2-Aryl-3-(6-trifluoromethoxy)benzo[d]thiazole-based thiazolidinone hybrids as potential anti-infective agents: Synthesis, biological evaluation and molecular docking studies. Bioorg. Med. Chem. Lett. 2021, 32, 127718. [Google Scholar] [CrossRef]
  9. Pal, N.; Arya, A.K. An efficient and facile synthesis of Zn(II) complexes with 2-substituted benzothiazoles and glycine- and alanine-based ligands having antifungal and antibacterial activities. Res. Chem. Intermed. 2013, 39, 553–560. [Google Scholar] [CrossRef]
  10. Gilani, S.J.; Hassan, M.Z.; Imam, S.S.; Kala, C.; Dixit, S.P. Novel benzothiazole hydrazine carboxamide hybrid scaffolds as potential in vitro GABA AT enzyme inhibitors: Synthesis, molecular docking and antiepileptic evaluation. Bioorg. Med. Chem. Lett. 2019, 29, 1825–1830. [Google Scholar] [CrossRef]
  11. Tang, X.; Wang, Z.B.; Zhong, X.M.; Wang, X.B.; Chen, L.J.; He, M.; Xue, W. Synthesis and biological activities of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety. Phosphorus Sulfur Silicon Relat. Elem. 2019, 194, 241–248. [Google Scholar] [CrossRef]
  12. Miralinaghi, P.; Schmitt, C.; Hartmann, R.W.; Frotscher, M.; Engel, M. 6-Hydroxybenzothiophene ketones: Potent inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) owing to favorable molecule geometry and conformational preorganization. ChemMedChem 2014, 9, 2294–2308. [Google Scholar] [CrossRef]
  13. Spadaro, A.; Negri, M.; Marchais-Oberwinkler, S.; Bey, E.; Frotscher, M. Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17 beta-hydroxysteroid dehydrogenase Type 1 (17 beta-HSD1). PLoS ONE 2012, 7, e292522012. [Google Scholar] [CrossRef] [Green Version]
  14. Spadaro, A.; Frotscher, M.; Hartmann, R.W. Optimization of hydroxybenzothiazoles as novel potent and selective inhibitors of 17 beta-HSD1. J. Med. Chem. 2012, 55, 2469–2473. [Google Scholar] [CrossRef] [PubMed]
  15. Komiya, M.; Asano, S.; Koike, N.; Koga, E.; Igarashi, J.; Nakatani, S.; Isobe, Y. Synthesis of novel benzo-fused heteroaryl derivatives as Ca2+/Calmodulin-dependent protein kinase II inhibitors. Chem. Pharm. Bull. 2013, 61, 1094–1097. [Google Scholar] [CrossRef] [Green Version]
  16. Myllymaki, M.J.; Saario, S.M.; Kataja, A.O.; Castillo-Melendez, J.A.; Nevalainen, T.; Juvonen, R.O.; Jarvinen, T.; Koskinen, A.M.P. Design, synthesis, and in vitro evaluation of carbamate derivatives of 2-benzoxazolyl- and 2-benzothiazolyl-(3-hydroxyphenyl)-methanones as novel fatty acid amide hydrolase inhibitors. J. Med. Chem. 2007, 50, 4236–4242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Tang, G.Z.; Nikolovska-Coleska, Z.; Qiu, S.; Yang, C.Y.; Guo, J.; Wang, S.M. Acylpyrogallols as inhibitors of antiapoptotic Bcl-2 proteins. J. Med. Chem. 2008, 51, 717–720. [Google Scholar] [CrossRef] [PubMed]
  18. Chen, J.J.; Li, C.M.; Wang, J.; Ahn, S.; Wang, Z.; Lu, Y.; Dalton, J.T.; Miller, D.D.; Li, W. Synthesis and antiproliferative activity of novel 2-aryl-4-benzoyl-imidazole derivatives targeting tubulin polymerization. Bioorg. Med. Chem. 2011, 19, 4782–4795. [Google Scholar] [CrossRef] [Green Version]
  19. Hu, E.; Kunz, R.K.; Chen, N.; Rumfelt, S.; Siegmund, A.; Andrews, K.; Chmait, S.; Zhao, S.; Davis, C.; Chen, H.; et al. Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A). J. Med. Chem. 2013, 56, 8781–8792. [Google Scholar] [CrossRef]
  20. Zhu, Y.P.; Jia, F.C.; Liu, M.C.; Wu, A.X.A. Multipathway coupled domino strategy: Metal-free oxidative cyclization for one-pot synthesis of 2-acylbenzothiazoles from multiform substrates. Org. Lett. 2012, 14, 4414–4417. [Google Scholar] [CrossRef]
  21. Fan, X.S.; He, Y.; Zhang, X.Y.; Guo, S.G.; Wang, Y.Y. Synthesis of heteroaryl ketones via tandem reaction of 1,1-dibromoethenes. Tetrahedron 2011, 67, 6369–6374. [Google Scholar] [CrossRef]
  22. Meng, X.; Bi, X.R.; Yu, C.Y.; Chen, G.X.; Chen, B.H.; Jing, Z.Q.; Zhao, P.Q. Ball-milling synthesized hydrotalcite supported Cu-Mn mixed oxide under solvent-free conditions: An active catalyst for aerobic oxidative synthesis of 2-acylbenzothiazoles and quinoxalines. Green Chem. 2018, 20, 4638–4644. [Google Scholar] [CrossRef]
  23. Huynh, T.V.; Doan, K.V.; Luong, N.T.K.; Nguyen, D.T.P.; Doan, S.H.; Nguyen, T.T.; Phan, N.T.S. New synthesis of 2-aroylbenzothiazoles via metal-free domino transformations of anilines, acetophenones, and elemental sulfur. RSC Adv. 2020, 10, 18423–18433. [Google Scholar] [CrossRef]
  24. Liu, S.W.; Chen, R.; Chen, H.; Deng, G.J. Iron-catalyzed 2-acylbenzothiazole formation from aryl ketones and benzothiazoles using oxygen as oxidant. Tetrahedron Lett. 2013, 54, 3838–3841. [Google Scholar] [CrossRef] [Green Version]
  25. Wang, J.; Zhang, X.Z.; Chen, S.Y.; Yu, X.Q. Iron-catalyzed arylation or aroylation of benzothiazoles with benzylic alcohols and aryl ketones. Tetrahedron 2014, 70, 245–250. [Google Scholar] [CrossRef]
  26. Feng, Q.; Song, Q.L. Chemoselective copper-catalyzed acylation of benzothiazoles with aryl methyl ketones. Adv. Synth. Catal. 2014, 356, 2445–2452. [Google Scholar] [CrossRef]
  27. Wang, B.; Zhang, Q.W.; Guo, Z.Q.; Ablajan, K. Iodine- and TBHP-promoted acylation of benzothiazoles under metal-free conditions. Synthesis 2020, 52, 3058–3064. [Google Scholar]
  28. Hua, M.; Wang, C.Q.; Liu, Q.X.; Chen, D.Y.; Fu, H.; Zhou, H.F. Silver-mediated 2-arylation/alkylation/acylation of benzothiazoles with aldehydes in water. Heterocycles 2018, 96, 1226–1237. [Google Scholar]
  29. Yang, K.; Zhang, C.; Wang, P.; Zhang, Y.; Ge, H.B. Nickel-catalyzed decarboxylative acylation of heteroarenes by sp2 C-H functionalization. Chem.-Eur. J. 2014, 20, 7241–7244. [Google Scholar] [CrossRef]
  30. Yang, K.; Chen, X.Y.; Wang, Y.Q.; Li, W.Q.; Kadi, A.A.; Fun, H.K.; Sun, H.; Zhang, Y.; Li, G.G.; Lu, H.J. Cobalt-catalyzed decarboxylative 2-benzoylation of oxazoles and thiazoles with alpha-oxocarboxylic acids. J. Org. Chem. 2015, 80, 11065–11072. [Google Scholar] [CrossRef]
  31. Huang, T.H.; Wu, X.; Yu, Y.B.; An, L.; Yin, X.X. A convenient synthesis of 2-acyl benzothiazoles/thiazoles from benzothiazole/thiazole and N,N′-carbonyldiimidazole activated carboxylic acids. Tetrahedron Lett. 2019, 60, 1667–1670. [Google Scholar] [CrossRef]
  32. Lassalas, P.; Marsais, F.; Hoarau, C. DMAP-catalyzed regel-type direct C-2 (hetero)aroylation of oxazoles and thiazoles derivatives with acid chlorides. Synlett 2013, 24, 2233–2240. [Google Scholar] [CrossRef]
  33. Wirth, T. Hypervalent iodine chemistry in synthesis: Scope and new directions. Angew. Chem. Int. Edit. 2005, 44, 3656–3665. [Google Scholar] [CrossRef] [PubMed]
  34. Richardson, R.D.; Wirth, T. Hypervalent iodine goes catalytic. Angew. Chem. Int. Edit. 2006, 45, 4402–4404. [Google Scholar] [CrossRef]
  35. Merritt, E.A.; Olofsson, B. Alpha-functionalization of carbonyl compounds using hypervalent iodine reagents. Synthesis 2011, 517–538. [Google Scholar] [CrossRef] [Green Version]
  36. Lu, Q.; Sun, X.T.; Kong, Y.L.; Liu, J.C.; Chen, B.; Weng, J.Q. C2-arylacylation of 2H-benzothiazoles with methyl arenes via selectfluor oxidation. Tetrahedron Lett. 2021, 75, 153184. [Google Scholar] [CrossRef]
  37. Weng, J.Q.; Xu, W.X.; Dai, X.Q.; Zhang, J.H.; Liu, X.H. Alkylation reactions of benzothiazoles with N,N-dimethylamides catalyzed by the two-component system under visible light. Tetrahedron Lett. 2019, 60, 390–396. [Google Scholar] [CrossRef]
  38. Xu, W.X.; Dai, X.Q.; Weng, J.Q. K2S2O8-mediated hydroxyalkylation of benzothiazoles with alcohols in aqueous solution. ACS Omega 2019, 4, 11285–11292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Kong, Y.L.; Xu, W.X.; Liu, X.H.; Weng, J.Q. Visible light-induced hydroxyalkylation of 2H-benzothiazoles with alcohols via selectfluor oxidation. Chin. Chem. Lett. 2020, 31, 3245–3249. [Google Scholar] [CrossRef]
  40. Xu, W.X.; Ye, F.X.; Liu, X.H.; Weng, J.Q. NCS/TBHP promoted C2 arylation of benzothiazoles with aldehydes in DMSO. Tetrahedron Lett. 2020, 61, 151807. [Google Scholar] [CrossRef]
  41. Zhu, Y.P.; Liu, M.C.; Jia, F.C.; Yuan, J.J.; Gao, Q.H.; Lian, M.; Wu, A.X. Metal-free sp3 C-H bond dual-(het)arylation: I2-promoted domino process to construct 2,2-bisindolyl-1-arylethanones. Org. Lett. 2012, 14, 3392–3395. [Google Scholar] [CrossRef]
  42. Ghorbani-Choghamarani, A.; Taherinia, Z. New revolution in biaryl synthesis: Transition metal-free C-C bond formation promoted by the mixture of 2-mercaptoethanol/KOH/DMSO. ChemistrySelect 2019, 4, 4735–4738. [Google Scholar] [CrossRef]
  43. Matcha, K.; Antonchick, A.P. Metal-free cross-dehydrogenative coupling of heterocycles with aldehydes. Angew. Chem. Int. Edit. 2013, 52, 2082–2086. [Google Scholar] [CrossRef] [PubMed]
  44. Yang, Q.M.; Han, X.L.; Zhao, J.Q.; Zhang, H.Y.; Zhang, Y.C. Direct C3 Alkoxylation of Quinoxalin-2(1H)-ones with Alcohols via Cross-Dehydrogenative Coupling under Catalyst-Free Conditions. J. Org. Chem. 2019, 84, 11417–11424. [Google Scholar] [CrossRef] [PubMed]
  45. Li, X.; Liu, C.Y.; Guo, S.X.; Wang, W.; Zhang, Y.Q. PIFA-mediated cross-dehydrogenative coupling of N-heteroarenes with cyclic ethers: Ethanol as an efficient promoter. Eur. J. Org. Chem. 2021, 2021, 411–421. [Google Scholar] [CrossRef]
  46. Zhang, S.S.; Wang, S.W.; Leng, Y.T.; Wu, Y.J. One-pot synthesis of 2-acylbenzothiazoles from 2-aminobenzenethiols and arylacetonitriles via cyclization and sequential oxidation. Tetrahedron Lett. 2021, 79, 153300. [Google Scholar] [CrossRef]
  47. Fukuda, K.; Hasegawa, T.; Kotani, T.; Muramoto, H.; Okamoto, K. Benzothiazole Derivatives. U.S. Patent 5,900,426, 4 May 1999. [Google Scholar]
  48. Ma, R.C.; Ding, Y.X.; Chen, R.; Wang, Z.M.; Wang, L.; Ma, Y.M. Oxidant/solvent-controlled I2-catalyzed domino annulation for selective synthesis of 2-aroylbenzothiazoles and 2-arylbenzothiazoles under metal-free conditions. J. Org. Chem. 2021, 86, 310–321. [Google Scholar] [CrossRef]
Molecules 27 00726 g001 550
Figure 1. Several C2-arylacylated benzothiazole derivatives with potential as drug candidates.
Figure 1. Several C2-arylacylated benzothiazole derivatives with potential as drug candidates.
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Molecules 27 00726 g002 550
Figure 2. Representative arylacylation reactions of 2H-benzothiazoles.
Figure 2. Representative arylacylation reactions of 2H-benzothiazoles.
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Molecules 27 00726 g003 550
Figure 3. Gram-scale synthesis.
Figure 3. Gram-scale synthesis.
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Molecules 27 00726 g004 550
Figure 4. (a) Scope of substituted acetophenones. a a Reaction conditions: 1a (1.5 eq., 0.45 mmol), 2 (0.30 mmol), PIFA (2.0 eq., 0.60 mmol), KOH (1.0 eq., 0.30 mmol), DMSO/H2O (v/v, 3/1, 2 mL), 85 °C, 10 h; (b) Scope of substituted benzothiazoles and substituted acetophenones. b b Reaction conditions: 1 (1.5 eq., 0.45 mmol), 2 (0.30 mmol), PIFA (2.0 eq., 0.60 mmol), KOH (1.0eq., 0.30 mmol), DMSO/H2O (v/v, 3/1, 2 mL), 85 °C, 10 h.
Figure 4. (a) Scope of substituted acetophenones. a a Reaction conditions: 1a (1.5 eq., 0.45 mmol), 2 (0.30 mmol), PIFA (2.0 eq., 0.60 mmol), KOH (1.0 eq., 0.30 mmol), DMSO/H2O (v/v, 3/1, 2 mL), 85 °C, 10 h; (b) Scope of substituted benzothiazoles and substituted acetophenones. b b Reaction conditions: 1 (1.5 eq., 0.45 mmol), 2 (0.30 mmol), PIFA (2.0 eq., 0.60 mmol), KOH (1.0eq., 0.30 mmol), DMSO/H2O (v/v, 3/1, 2 mL), 85 °C, 10 h.
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Molecules 27 00726 g005 550
Figure 5. Mechanistic experiments.
Figure 5. Mechanistic experiments.
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Molecules 27 00726 g006 550
Figure 6. Plausible mechanism.
Figure 6. Plausible mechanism.
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Table
Table 1. Optimization of reaction conditions a.
Table 1. Optimization of reaction conditions a.
Molecules 27 00726 i001
EntryOxidant (eq.)Base (eq.)Solvent (mL)Yield (%) b
1PIFA (2)NaOH (1)DMSO (2)7
2PIFA (2)NaOH (1)MeCN (2)N.D.
3PIFA (2)NaOH (1)DMF (2)N.D.
4PIFA (2)NaOH (1)H2O (2)N.D.
5PIFA (2)NaOH (1)DMSO/H2O 1:1 = (2)36
6PIFA (2)NaOH (1)DMSO/H2O 2:1 = (2)48
7PIFA (2)NaOH (1)DMSO/H2O 3:1 = (2)60
8PIFA (2)NaOH (1)DMSO/H2O 4:1 = (2)53
9PIFA (2)K2CO3 (1)DMSO/H2O 3:1 = (2)35
10PIFA (2)Na2CO3 (1)DMSO/H2O 3:1 = (2)32
11PIFA (2)KOH (1)DMSO/H2O 3:1 = (2)75
12PIFA (2)noneDMSO/H2O 3:1 = (2)N.D.
13PIFA (2)KOH (0.5)DMSO/H2O 3:1 = (2)48
14PIFA (2)KOH (1.5)DMSO/H2O 3:1 = (2)53
15noneKOH (1)DMSO/H2O 3:1 = (2)N.D.
16PIFA (0.5)KOH (1)DMSO/H2O 3:1 = (2)26
17PIFA (1.5)KOH (1)DMSO/H2O 3:1 = (2)38
18PIFA (2.5)KOH (1)DMSO/H2O 3:1 = (2)51
19 cPIFA (2)KOH (1)DMSO/H2O 3:1 = (2)58
20 dPIFA (2)KOH (1)DMSO/H2O 3:1 = (2)65
21 ePIFA (2)KOH (1)DMSO/H2O 3:1 = (2)86
22 fPIFA (2)KOH (1)DMSO/H2O 3:1 = (2)85
a Reaction conditions: 1a (1.5 eq., 0.45 mmol), 2a (0.30 mmol), oxidant, base in solvent at 85 °C for 8 h. b isolated yield. c 75 °C. d 95 °C. e 10 h. f 12 h.
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Sun, X.-T.; Hu, Z.-G.; Huang, Z.; Zhou, L.-L.; Weng, J.-Q. A Novel PIFA/KOH Promoted Approach to Synthesize C2-arylacylated Benzothiazoles as Potential Drug Scaffolds. Molecules 2022, 27, 726. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030726

AMA Style

Sun X-T, Hu Z-G, Huang Z, Zhou L-L, Weng J-Q. A Novel PIFA/KOH Promoted Approach to Synthesize C2-arylacylated Benzothiazoles as Potential Drug Scaffolds. Molecules. 2022; 27(3):726. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030726

Chicago/Turabian Style

Sun, Xiao-Tong, Zhi-Gang Hu, Zhen Huang, Ling-Li Zhou, and Jian-Quan Weng. 2022. "A Novel PIFA/KOH Promoted Approach to Synthesize C2-arylacylated Benzothiazoles as Potential Drug Scaffolds" Molecules 27, no. 3: 726. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030726

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