Syntheses of 2-Aryl Benzothiazoles via Photocatalyzed Oxidative Condensation of Amines with 2-Aminothiophenol in the Presence of BODIPY Derivatives

Abstract A simple, convenient, and efficient new method for synthesis of 2-aryl benzothiazoles under mild conditions with nonmetal catalyst has been developed. Boron–dipyrromethene (BODIPY) dyes were used as photocatalysts for aerobic oxidative reactions of amine with 2-aminothiophenol. The approach will be very useful for the synthesis of benzothiazole derivatives and the development of photocatalytic reactions. GRAPHICAL ABSTRACT


INTRODUCTION
2-Aryl benzothiazoles play a very important role as organic functional materials in chemistry and are also widely used as biologically active products, [1,2] as well as marketed drugs or drug candidates. [3] For example, 2-aryl benzothiazoles are not only important fluorescent dyes that are used in fiber and plastic [4] but also are used as liquid crystals and off-color material. [5,6] In medicine, 2-aryl benzothiazoles serve as fungicides, [7] acaricides, [8] and anticancer agents. [9] Some synthesis methods for 2-aryl benzothiazoles have been reported in the literature. [10][11][12][13][14][15][16][17] Classic methods for the synthesis involve the condensation of 2-aminothiophenols with aryl aldehydes, [10] acyl chlorides, [11] carboxylic acids, [12] alcohols, [13] and amines [14] in the presence of oxidants. Another method is intramolecular cyclization reaction of N- (2-bromophenyl)benzothioamide with the Pd complex as catalyst. Moreover, it also has been demonstrated that 2-aryl benzothiazoles can be synthesized efficiently via transition-metal-catalyzed (Ni, Pd) cross-couplings between benzothiazoles and aryl halides, [15] aryl boronic acids, [16] or aromatic carboxylic acids. [17] Unfortunately, so many disadvantages, such as rigorous conditions (i.e., high temperature, long reaction time, and high pressure), hazardous oxidants, [18] or potential toxicity and high cost of the metal catalysts, presented in these synthetic reactions, result in transformations that are uneconomical and unfriendly to the environment. Therefore, a new method for its construction is highly desirable.
With the demand for green chemistry, visible-light-responsive photoredox reactions show much prominence for the use of the visible light, which is a clean energy source provided by the solar irradiance. Boron-dipyrromethene (BODIPY) is a class of novel fluorescent dyes. It is composed of dipyrromethene complexes with a substituted boron atom, typically a BF 2 unit. [19,20] Currently, BODIPY has been used as visible-light-responsive photocatalyst applied in oxidation of thioanisole and dihydroxylnaphthalenes, [21,22] which shows excellent photocatalytic activity. In these reactions, oxygen=air was used as the terminal oxidant. Mild conditions and metal-free photoredox reaction driven by the BODIPY photosensitizer make it highly economical for their excellent properties such as strong fluorescence and absorption. Meanwhile, the molecular structure of BODIPY can be so easily tuned by a way of small modifications that we can choose a better catalyst to photocatalyze the oxidative reaction. In this context, one-pot synthesis of 2-aryl benzothiazoles via BODIPY-photocatalyzed oxidation of amines with 2-aminothiophenol in visible light was explored.

RESULTS AND DISCUSSION
There are several BODIPY photocatalysts discussed in this article. As shown in Scheme 1, BODIPY 1 is made from aldehyde as electrophilic component to form the methane bridge between two pyrrole units. Then BODIPY 2 and BODIPY 3 are synthesized by using copper(II) bromide as bromination reagents in mild conditions Scheme 1. Synthesis of BODIPYs.

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Z. ZHOU AND W. YANG with excellent yields and selectivity. Their structures are confirmed by the 1 H NMR, 13 C NMR, and mass (MS) spectra. With BODIPYs in hand, we further studied the photophysical properties of these compounds. BODIPYs are colorful to our eyes, and most of them are brilliant upon irradiation. UV-vis absorption and fluorescence spectra of BODIPYs were studied (see Fig. 1). BODIPYs' spectra show the typical narrow absorption and sharp fluorescence emission bands of classic difluoroboron dipyrrins, and the maximum fluorescence emission band (BODIPY 3b, the blue dashed line in Fig. 1) can approach 580 nm, which displays near-IR emission. With the increased conjugation on BODIPY b molecule, the spectra are red-shifted (10 nm for absorption and 10 nm for fluorescence emission) compared with those of BODIPY a. Meanwhile, with the increase of the amount of bromine atom in the BODIPY structure, obvious red shifts of the absorption and emission was observed in BODIPY 3a, and the Stokes shift are 10 nm and 20 nm respectively compared with BODIPY 1a and BODIPY 2a.
On the other hand, fluorescence quantum yield was weakened to a great extent for this reason (see Table 1). To solve the problems that occur in synthesis of 2-aryl benzothiazoles mentioned previously, one-pot synthesis of 2-aryl benzothiazoles via BODIPYphotocatalyzed oxidation of amines with 2-aminothiophenol in visible light was explored. We are aimed at accomplishing the transformation effectively under a mild condition with nonmetal catalyst.
Results of control experiments and optimization of reaction conditions for the oxidation of benzylamine are shown in Table 2. Initially, the reaction was conducted without visible light ( Table 2, entry 6), and no product was detected in gas chromatography (GC). Similarly, no transformation occurred in the absence of oxygen even with longer reaction time to 8 h ( Table 2, entry 5). When the reaction was conducted under light without BODIPY catalyst, no product was observed either ( Table 2, entry  7). Meanwhile, we also found the mounts of 2-aminothiophenol (from 2 to 3 eq) and  the reaction atmosphere (air to O 2 ) just have a slight effect on the reaction results, for the yields only rise 2% and 3% respectively. Therefore, the conclusion was made as follows: the light, photosensitizer, and oxygen are essential to the photocatalytic oxidation. Subsequently, a better yield (80%) was obtained with temperature rising to 50 C ( Table 2, entry 4). We further raised the reaction temperature to 80 C ( Table 2, entry 10), and GC shows that more side products were generated (the main side product is benzaldehyde). By changing the photosensitizer, however, compared with BODIPY 1 and BODIPY 2, it is obvious that BODIPY 3 presents significant influences in the aerobic oxidation of benzylamine with 2-aminothiophenol at the same condition ( Table 2, entries 1-3). As the amount of bromine in the BODIPY structure increases, better yields are obtained, which may suggest that bromine can promote the generation of 1 O 2 in accordance with some reported results that the bromine-substituted BODIPY strongly promoted the generation of 1 O 2 . [23,24] Based on these results, we decided to set heating the benzylamine and 2-aminothiophenol at 50 C in the presence of BODIPY 3a irradiated by a 35-W xenon lamp as our optimized condition.
With the optimized protocol results in hand, a number of experiments were carried out to explore the scope and limitation of the reaction (Table 3). We found that the reaction worked very well for a wide variety of substituted benzylamines, obtaining the expected substituted benzothiazoles in yields ranging from 42 to 81%. With various substituents such as methyl, chloro, fluoro, bromine, and methoxy as well as naphthyl, all groups proceeded smoothly in good yields. For example, benzylamines substituted with electron-donating groups (CH 3 and OCH 3 ) (Table 3, entries 3, 4, and 11) afford the target products in 78-81% yields. Halogens such as chloro and bromine (Table 3, entries 6, 9, and 10) give no problems for para-substituted benzylamines, meta or ortho, except the fluoro (Table 3, entries 2 and 7), which are strong electron-withdrawing groups and only undergo the oxidative condensation with 42% yields. So the oxidation of the electron-donating groups proceeded more efficiently than the electron-withdrawing groups. We also found that no reaction occurred when amine lacked a-H, such as aniline (Table 3, entry 15). Heterocyclic amine, such as thiophen-2-ylmethanamine, also proceeded smoothly with better yield.
Based on these foregoing results, we proposed a mechanism that it is highly likely that the presence of singlet oxygen ( 1 O 2 ) [25] is responsible for the photooxidation of benzylamine with 2-aminophenol. We further studied the influence of DABCO (1,4-diazabicyclo[2.2.2]octane, a singlet oxygen scanvenger) to the oxidation. We found that the photocatalytic reaction can be significantly quenched by the DABCO (Table 4). Therefore, we think 1 O 2 is involved in the photooxidative process. The proposed mechanism is shown in Scheme 2. First, BODIPY accepted a photon from the visible light to form BODIPY Ã under the irradiation by visible light. Then, benzylamine was oxidized to form phenylmethanimine by singlet oxygen generated by energy transfer from BODIPY Ã . Finally, 2-aryl benzothiazole was formed by the condensation of intermediate. Some details about the singlet oxygen involved in the photosensitized oxidation reaction had been reported and discussed. [26,27] In terms of the energy requirements, BODIPY dyes generating singlet oxygen from the triplet excited state have been used in photodynamic therapy. [28][29][30] In summary, several BODIPY dyes were synthesized, and their structures were confirmed by 1 H NMR, 13 C NMR, and MS spectra, and they were used as photocatalysts for aerobic oxidative reactions of amine with 2-aminothiophenol. A new method to synthesize 2-aryl benzothiazoles under a mild condition with a metal-free procedure using BODIPY as photocatalysts was developed. Our   Aryl-aldehyde (2.0 mmol) and 2,4-dimethylpyrrole (423 mg, 4.5 mmol) were dissolved in (100 mL) absolute CH 2 Cl 2 . Trifluoroacetic acid (one drop) was added in the solution under argon. After the reaction mixture was stirred about 4 h at room temperature until thin-layer chromatography (TLC) showed the complete consumption of the aldehyde. Then DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) (454 mg, 2.0 mmol) in CH 2 Cl 2 (50 mL) was added. The mixture was stirred for 30 min followed by the addition of Et 3 N (6 mL) and BF 3 Á Et 2 O (4 mL) at ice-cold condition and further stirred at room temperature for 3 h. The reaction mixture was washed with water (3 Â 100 mL), and then the organic layers were combined, dried with anhydrous MgSO 4 , and evaporated to dryness. The crude product was further purified using column chromatography.
General Procedure for BODIPY 2 1,3,5,7-Tetramethyl-BODIPY 1 (0.2 mmol) and K 2 CO 3 (0.6 mmol) were dissolved in MeCN (20 mL). CuBr 2 (0.3 mmol) in MeCN (25 mL) was slowly added in the solution under an O 2 atmosphere (balloon). The mixture was stirred at rt for 24 h. The reaction mixture was washed with EtOAc (3 Â 40 mL) and then washed with H 2 O (3 Â 30 mL). The organic layer were combined and dried over with anhydrous MgSO 4 and evaporated to dryness. The crude product was further purified using column chromatography.

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Z. ZHOU AND W. YANG anhydrous MgSO 4 , and evaporated to dryness. The crude product was further purified using column chromatography.

Typical Procedures for Photocatalytic Oxidation of Amine with 2-Aminothiophenol
Amine (1 mmol), 2-aminothiophenol (2 mmol), BODIPY photosensitizer (0.01 mmol, 1.0 mol%), and acetonitrile (5 mL) were added to a dry 10-mL flask. The flask was pressurized with air (2 bar) and then heated to 50 C. The solution was then irradiated using a 35-W xenon lamp through a cutoff filter (0.72 M NaNO 2 aqueous solution, which is transparent for light >385 nm, because lamps could emit a small amount of ultraviolet light). After the reaction was completed, the solvent was evaporated under reduced pressure. The crude product was further purified using column chromatography.

SUPPORTING INFORMATION
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