Synthesis of Benzothiazoles Using Fluorescein As An Efficient Photocatalyst
Synthesis of Benzothiazoles Using Fluorescein As An Efficient Photocatalyst
Synthesis of Benzothiazoles Using Fluorescein As An Efficient Photocatalyst
Molecular Catalysis
journal homepage: www.journals.elsevier.com/molecular-catalysis
A R T I C L E I N F O A B S T R A C T
Keywords: This work reports a novel and efficient method for the synthesis of benzothiazoles using 2-aminothiophenol
Benzothiazoles derivatives in conjunction with aromatic aldehyde as starting materials via visible-light-induced condensation
Visible-light-induced cyclization. Utilizing fluorescein as the photocatalyst and blue LED lamp as the light source, the reaction pro
Fluorescein
ceeds in the presence of a molecular oxygen atmosphere without the need for metal catalyst or an additional
Photocatalyst
oxidant. Significantly, this method exhibits good tolerance in substrates, and a variety of 2-aminothiophenol
derivatives and aromatic aldehyde are amenable to producing the corresponding benzothiazoles in high to
excellent yields.
1. Introduction Cu2O, [18] ZnO nanoparticles, [19] and YCl3 [20] were also previously
reported (Scheme 1, eq. (3)). Although many methods have been used to
Benzothiazoles are a valuable class of heterocyclic compounds in synthesize benzothiazoles to date, they often suffer from some re
organic chemistry, and its derivatives due to their building blocks in strictions in aspects such as additional additives, excess amounts of
biological and therapeutic activities are vital core structures used to oxidant, expensive metal catalysts, limited starting materials, harsh re
create drugs, for instance anticancer, antiviral antihistamine, antiulcer, action conditions or effect on the environment. [21–22] In consequence,
antifungal, anti-inflammatory, anti-convulsant, antimicrobial, enzyme the pursuit of alternative efficient methods to obtain benzothiazoles has
inhibition, etc. [1–5] Benzothiazole rings are also found in a myriad of never ceased.
natural products, for example vitamin B12. [6] Moreover, benzothia In recent years, visible light, as a readily available and renewable
zoles are applied in materials science as the core components of mate clean energy source, has attracted extensive attention in assisting cata
rials with optical or electronic properties, and also used as ligands of lytic organic synthesis reactions. [23–25] Notably, organic dyes are
transition metals and intermediates of organic reactions. [7–9] Hence, cheaper and more reliable than some expensive metal photocatalysts in
the development of simple and practical methods to synthesize benzo many valuable reactions. [26–27] In the present paper, a novel, efficient
thiazoles and its derivatives has stimulated considerable interest, which and green method for the synthesis of benzothiazoles under visible light
is precisely based on their great application prospects. is reported (Scheme 1, eq. (4)). Owing to its cheap and commercially
Over the past decades, different routes for the synthesis of benzo available characteristics, fluorescein has been selected as the photo
thiazoles have been developed using various catalytic systems because catalyst. The synthesis of benzothiazoles would proceed in the presence
of their wide range of applications. [10–12] Among these strategies, the of visible light, fluorescein and a molecular oxygen atmosphere without
condensation of 2-aminothiophenol with aromatic aldehyde are of the the need for metal catalyst or an additional oxidant. We suppose the
most commonly used methods, and a number of Brønsted acids, namely, present work could make the reaction more synthetically accessible by
[bsmim] [HSO4,13] [DodecIm] [HSO4,14] and BAIL gel [15] have been eliminating the requirement for high temperature, strong acid and use of
used as the acid catalyst (Scheme 1, eq. (1)). In some cases, an excess of metal catalyst.
oxidants, such as DTBP, [16] TBHP, [13] and, DDQ [17] were also
employed in the reaction, which could lead to several side reactions and 2. Results and discussion
difficult separation of the products from the reaction mixture (Scheme 1,
eq. (2)). In addition to these, different metal catalytic systems, such as In our initial studies towards the synthesis of benzothiazoles, 2-
* Corresponding author.
E-mail address: sunwuji@yeah.net (W. Sun).
https://doi.org/10.1016/j.mcat.2021.111693
Received 24 February 2021; Received in revised form 28 May 2021; Accepted 31 May 2021
Available online 18 June 2021
2468-8231/© 2021 Elsevier B.V. All rights reserved.
W. Sun et al. Molecular Catalysis 510 (2021) 111693
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W. Sun et al. Molecular Catalysis 510 (2021) 111693
Table 2
Scope and generality of photocatalytic condensation reactionsa.
a
Reaction conditions: 1a-1b (1 mmol), 2a-2j (1 mmol), fluorescein (10 mol%), CH3OH (20 mL), blue LED at room temperature, under air atmosphere.
aromatic aldehydes with multiple substituents gave a lower yield which need for an additional oxidant (Scheme 2, eq. (5)).
may be due to the presence of two electron-donating groups on the ar Based on the above experimental results and literature reports, [26,
omatic aldehydes (Table 2, 3j). 28] one reasonable process has been proposed to explain the formation
Next, these conditions were then applied to 2-aminothiophenol de of product 3a. The proposed mechanism begins with the formation of
rivative and found that they were well tolerated under the present re imine I, which is obtained by nucleophilic addition and dehydrated of
action conditions. The reaction of 2-amino-4-chlorothiophenol 1b with 2-aminothiophenol 1a and benzaldehyde 2a under blue LED irradiation.
benzaldehyde 2a under the optimized conditions produced the corre Subsequently, the resulting intermediate I undergoes intramolecular
sponding product 3k in 89% yield (Table 2, 3k). The use of 2-amino-4- cyclization, generating intermediate II. Under the fluorescein/O2 cata
chlorothiophenol 1b proceeded smoothly with various substituted aro lyst system, fluorescein (Fl) generates excited fluorescein* (Fl*) species
matic aldehydes containing both electron-withdrawing and electron- under visible light, and intermediate II is converted to intermediate III
donating groups, with 83–93% yields (Table 2, 3l-3t). via single electron transfer. Fluorescein radical anion (Fl*− ) is oxidized
In order to explain the reaction mechanism, some control experi to ground state fluorescein (Fl) by O2. Finally, the desired product 3a is
ments were conducted (Scheme 2). The first experiment under the produced by deprotonation of intermediate III and hydrogen
optimized condition gave 3a in a good yield (92%) with that of the same abstraction.
compound obtained in the studied approach (Scheme 2, eq. (1)). As can
be seen from eq. (2), the desired product 3a was not produced in the 3. Conclusions
system, indicating the importance of the photocatalyst. According to eq.
(3), the photocatalytic condensation reactions revealed that the reaction In summary, we developed a novel, efficient and green method for
was almost completely inhibited in the absence of light. Under similar synthesis of benzothiazoles via the visible-light-induced condensation
conditions but in an argon atmosphere, no desired product was detect cyclization of 2-aminothiophenol derivatives and aromatic aldehyde
able (Scheme 2, eq. (4)). Moreover, when TBHP was added to the above using fluorescein as photocatalyst. The reactions proceeded smoothly,
reaction mixture, the desired product 3a was obtained in a 93% yield. It affording the corresponding benzothiazoles in high to excellent yields
is indicated that TBHP and a molecular oxygen atmosphere have a with good functional group tolerance. Moreover, the catalytic system
similar impact on the studied reaction, and the reaction affords a good avoids the use of an additional oxidant or metal catalyst, in line with the
yield in the presence of a molecular oxygen atmosphere without the concept of green chemistry. The application of this method for
3
W. Sun et al. Molecular Catalysis 510 (2021) 111693
preparation of other useful heterocycles is underway in our laboratory. placed in a flat quartz glass jar. The open-air reaction container was
placed under a 30 W blue LED lamp. After completion of the reaction
4. Experimental (monitored by TLC analysis), the solvent was removed under reduced
pressure. Then, water (20 mL) was added and the mixture was extracted
4.1. Chemistry with ethyl acetate (3 × 20 mL). The combined organic layer was dried
over anhydrous Na2SO4 and the solvent was removed in vacuo. The
All of the chemicals were purchased from commercial sources and crude product was purified via silica gel column chromatography (pe
used without further purification. The reactions were monitored by thin troleum ether/ethyl acetate rations of 4:1–6:1) to generate the corre
layer chromatography (TLC), and the products were purified by column sponding product 3.
chromatography on silica gel (200–300 mesh). 1H NMR spectra were 2-Phenylbenzothiazole (3a). 92% yield as a white solid; 1H NMR
recorded on a Bruker Avance 400 spectrometer at 400 MHz in DMSO‑d6. (400 MHz, DMSO‑d6): δ (ppm) 8.18–8.13 (m, 1H), 8.13–8.07 (m, 3H),
The following abbreviations were used to describe peak splitting pat 7.60–7.55 (m, 4H), 7.50–7.46 (m, 1H); HRMS (ESI) m/z: calcd for
terns when appropriate: s = singlet, d = doublet, t = triplet, m = mul C13H10NS [M + H]+ 212.0528, found 212.0527.
tiple. Coupling constants (J) were reported in Hertz (Hz). Mass spectra 2-(2′-Bromophenyl)benzothiazole (3b). 90% yield as a white
(ESI-HRMS) were recorded using an Agilent Accurate-Mass Q-TOF LC/ solid; 1H NMR (400 MHz, DMSO‑d6): δ (ppm) 8.22–8.19 (m, 1H), 8.13
MS 6520 instrument with an ESI source. Fluorescence spectra of the (d, J = 8.7 Hz, 1H), 8.03 (dt, J = 7.7, 1.5 Hz, 1H), 7.89–7.86 (m, 1H),
synthesized compounds were taken using a CREE XPE-3535 fluores 7.62–7.57 (m, 2H), 7.55–7.48 (m, 2H); HRMS (ESI) m/z: calcd for
cence spectrophotometer. C13H9BrNS [M + H]+ 289.9634, found 289.9632.
2-(3′-Bromophenyl)benzothiazole (3c). 91% yield as a white
4.2. General procedure for synthesis of products 3a-3t solid; 1H NMR (400 MHz, DMSO‑d6): δ (ppm) 8.25 (dt, J = 7.4, 2.6 Hz,
1H), 8.20–8.15 (m, 1H), 8.11–8.08 (m, 2H), 7.81–7.77 (m, 1H),
2-Aminothiophenol derivatives 1 (1 mmol), aromatic aldehyde 2 (1 7.60–7.49 (m, 3H); HRMS (ESI) m/z: calcd for C13H9BrNS [M + H]+
mmol) and fluorescein (10 mol%) were dissolved in 20 mL methanol and 289.9634, found 289.9638.
4
W. Sun et al. Molecular Catalysis 510 (2021) 111693
5
W. Sun et al. Molecular Catalysis 510 (2021) 111693
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