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

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.


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 Ca 2+ /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 sp 2 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" 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 sp 2 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 CuIcatalyzed 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 2Hbenzothiazoles 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 metalfree.

Optimization of Reaction Conditions
Initially, we chose 2H-benzothiazole (1a) and acetophenone (2a) as the model sub- 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.

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 H 2 O (Table 1, entries 1-4). To our delight, the reaction efficiency was greatly improved when DMSO was mixed with H 2 O. The experimental results indicated that the product yield reached 60% in the mixture of DMSO and H 2 O 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 (  [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 (  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).

Entry
Oxidant (eq.) Base (eq.) Solvent (mL) PIFA (2)  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). 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).

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 parapositions gave the corresponding arylacylated products in 80-85% yields (Figure 4a

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 parapositions gave the corresponding arylacylated products in 80-85% yields (Figure 4a  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 electronwithdrawing 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), presuma- 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 electronwithdrawing 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.
sequently, 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].

Conclusions
In summary, we have developed a novel PIFA/KOH synergistically promoted C2arylacylation of 2H-benzothiazoles using aryl methyl ketones as carbonyl sources. This

Conclusions
In summary, we have developed a novel PIFA/KOH synergistically promoted C2arylacylation 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.

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 1 H-NMR and 125 MHz for 13 C-NMR) using TMS as an internal standard and CDCl 3 or DMSO-d 6 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.

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.