Hydrosilane-promoted cyclization of 2-aminothiophenols by CO₂ to benzothiazoles

Abstract

A new route is presented to synthesize benzothiazoles via cyclization of 2-aminothiophenols by CO₂ in the presence of diethylsilane catalyzed by 1,5-diazabicyclo[4.3.0]non-5-ene, and a series of benzothiazoles were obtained in good yields.

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Benzothiazole and its derivatives are very important biological and chemical intermediates due to their broad biological and pharmaceutical properties.¹ The traditional methods to synthesize benzothiazoles are based on the following reactions as illustrated in Scheme 1: (I) condensation of 2-aminothiophenol with carbonyl or cyano containing compounds like aryl ketones,² aromatic aldehydes,³ N-acylated benzotriazoles⁴ or nitriles (Scheme 1a);⁵ (II) reactions of 2-haloanilides with isothiocyanates,⁶ carbon disulfide and piperidine (Scheme 1b),⁷ aldehydes and sulfur,⁸ carbon disulfide and thiols,⁹ acid chlorides and Lawesson's reagent;¹⁰ (III) cyclization of thioformanilides,¹¹ o-haloarylthioureas¹² or o-iodothiobenzanilides (Scheme 1c)¹³ catalyzed by transition metals. These approaches suffer from their inherent limitations, such as low yields, poor selectivity, requiring harsh reaction conditions and harmful reagents, and using metal catalysts, etc. Therefore, it is highly desirable to develop metal-free and environmentally benign routes by using renewable and relatively green reagents for the synthesis of benzothiazoles.

Scheme 1 Strategies for the synthesis of benzothiazoles.

As a safe, abundant, cheap, and renewable C1 building block,¹⁴ CO₂ has been used in organic synthesis for the construction of C–N, C–C, C–O, C–H chemical bonds, and value-added chemicals such as ureas,¹⁵ amides,¹⁶ carbonates,¹⁷ methanol,¹⁸ formic acid¹⁹ have been synthesized. However, due to its inherent thermodynamic stability and kinetic inertness, the activation of CO₂ is difficult. Therefore, much work has been focused on the activation of CO₂. It was reported that organic bases with tertiary nitrogen could react with CO₂ to form the carbamate species, resulting in the activation of CO₂.²⁰ Recently, hydrosilylation of CO₂ with hydrosilanes has made the CO₂ conversion proceed under mild conditions, showing that CO₂ could be activated by hydrosilanes.²¹ The combination of organic base and hydrosilane may provide new possibilities for efficient CO₂ chemical transformation.

As a part of our continual investigation on the chemical conversion of CO₂ into value-added chemicals via construction of C–N, C–C bonds,²² we herein presented the hydrosilane-promoted cyclization of 2-aminothiophenols with CO₂ to benzothiazoles catalyzed by organic base (Scheme 1d). In this protocol, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) served as a catalyst for activating CO₂ to react with hydrosilane to form silyl formate, which further reacted with 2-aminothiophenols, producing benzothiazoles. The reported reactions were successfully applied to the substituted 2-aminothiophenols, affording corresponding benzothiazoles in moderate to excellent yields. To the best of our knowledge, this is the first work on the synthesis of benzothiazoles via the cyclization of 2-aminothiophenols using CO₂ as a C1 resource.

2-Aminothiophenol as a model substrate was investigated to react with CO₂ in the presence of hydrosilane under different conditions, and the results are summarized in Table 1. It was demonstrated that the reaction did not occur in the absence of any organic bases (Table 1, entry 1). To our delight, the reaction proceeded to form benzothiazole catalysed by organic bases including 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and DBN (Table 1, entries 2–4). Especially, benzothiazole was obtained in a yield of >90% catalysed by DBN in the presence of diethylsilane (Et₂SiH₂) in 1-methyl-2-pyrrolidinone (NMP) at 150 °C (Table 1, entry 4). A trace amount of benzothiazolone as byproduct was detected, which may result from the reaction of CO₂ with 2-aminothiophenol under the experimental conditions. Compared to DBN, TBD and DBU afforded lower yields of product, which may be ascribed to the joint effects of the basicity (TBD > DBU > DBN) and steric hindrance (DBN < TBD < DBU),²³ and the organic base with a relatively less steric hindrance was more active for catalysing this reaction. Hydrosilanes had considerable influences on the cyclization reaction of 2-aminothiophenol with CO₂ catalyzed by DBN. As PMHS (poly(methylhydrosiloxane)) was used, both the conversion of 2-aminothiophenol and the yield of benzothiazole decreased dramatically (Table 1, entry 5); while triethylsilane (Et₃SiH) afforded a product yield of 29% with 2-aminothiophenol conversion of 96% (Table 1, entry 6). These results suggested that Et₂SiH₂ was superior to other alkylsilanes for the synthesis of benzothiazole under the tested conditions. Consequently, DBN and Et₂SiH₂ were, respectively, chosen as catalyst and hydride donor to investigate the synthesis of benzothiazole under various conditions.

Table 1 Reaction of 2-aminothiophenol with CO₂ and hydrosilane under different conditions^a

Entry	Base	Hydrosilane	P/MPa	T/°C	Conv.^b/%	Yield^c/%
a Reaction conditions: 2-aminothiophenol, 2 mmol; base, 1 equiv.; hydrosilane (Si–H 10 equiv.); NMP, 2 mL; 24 h.b The loss of starting material as determined by ^1H NMR (DMSO-d6, 400 MHz) using 4-nitroacetophenone as an internal standard.c The conversion to product as determined by ^1H NMR (DMSO-d6, 400 MHz) using 4-nitroacetophenone as an internal standard.
1	—	Et2SiH2	5	150	0	0
2	TBD	Et2SiH2	5	150	78	73
3	DBU	Et2SiH2	5	150	88	70
4	DBN	Et2SiH2	5	150	92	90
5	DBN	PMHS	5	150	69	57
6	DBN	Et3SiH	5	150	96	29
7	DBN	Et2SiH2	7	150	91	81
8	DBN	Et2SiH2	5	130	90	81

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The influences of the CO₂ pressure and temperature on this reaction were studied. As the CO₂ pressure was increased from 5 to 7 MPa, the conversion of 2-aminothiophenol was almost unchanged, while the benzothiazole yield decreased from 90% to 81% (Table 1, entries 4 and 7), accompanied with the detectable benzothiazolone. This indicates that higher pressure promoted the reaction of CO₂ with 2-aminothiophenol, leading to the formation of benzothiazolone as byproduct. Temperature also had an impact on this reaction. As temperature was lowered from 150 to 130 °C, the yield of benzothiazole decreased to 81% (Table 1, entries 4 vs. 8), and more benzothiazolone was produced. Therefore, a CO₂ pressure of 5 MPa and temperature at 150 °C were selected for the synthesis of benzothiazole.

In the above experiments, benzothiazolone was detected as a byproduct, which was formed by the reaction of 2-aminothiophenol and CO₂. To suppress the formation of this byproduct, the influence of hydrosilane amount on the formation of benzothiazole was investigated. Fig. 1 shows the dependence of the yields of the benzothiazole and benzothiazolone on the molar ratio of Et₂SiH₂ to 2-aminothiophenol. It was obvious that benzothiazole was the main product under the tested conditions, and its yield was considerably affected by the amount of Et₂SiH₂. Increasing the hydrosilane amount from 1.5 to 5 equiv., the yield of benzothiazole increased from 70% to 90%, and the yield of benzothiazolone decreased from 22% to trace amount. These findings indicated that the formation of the byproduct could be restrained by enough hydrosilane.

Fig. 1 Influence of Et₂SiH₂ amount on the reaction. Reaction conditions: 2-aminothiophenol, 2 mmol; DBN, 1 equiv.; NMP, 2 mL; CO₂, 5 MPa; 150 °C; 24 h.

Encouraged by the above results, five substituted 2-aminothiophenols with electron-donating or electron-withdrawing groups were tested to react with CO₂ in the presence of Et₂SiH₂ using DBN as the catalyst in NMP (1-methyl-2-pyrrolidinone), and the results are listed in Table 2. To our delight, all the substrates could be transformed to the corresponding benzothiazoles. The reaction of 1a with CO₂ provided an isolated 2A yield of 82% under the selected reaction conditions (Table 2, entry 1). The substrate with electron-donating group (e.g., methyl) showed poor reactivity, affording a 2B yield of 55% even prolonging the reaction time to 72 h (Table 2, entry 2). In the case of 2-amino-5-methoxybenzenethiol as the substrate, the product yield reached 71% (Table 2, entry 3). The reactivity of the substrates with electron withdrawing groups was also investigated. Experimental results showed that 2-amino-5-bromobenzenethiol (1d) and 2-amino-4-chlorothiophenol (1e) could react smoothly with CO₂, giving isolated product yields of 78% and 72%, respectively (Table 2, entries 4 and 5). As for 5-aminolbenzothiazole (1f) as the substrate, the nitro group was further reduced to amino group, producing corresponding 5-aminolbenzothiazole (Table 2, entry 6) with a yield of 35%. It was worth noticing that only trace amount of substituted benzothiazolones as byproducts were detected in these reaction processes.

Table 2 Scope of the synthesis of various benzothiazoles^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: reactant, 2 mmol; DBN, 1 equiv.; Et2SiH2 (5 equiv.); NMP, 2 mL; CO2, 5 MPa; 150 °C; 24 h.b Yields of the isolated products.c Reaction time 72 h.
1			82
2			49/55^c
3			71
4			78
5			72
6			35

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In order to explore the reaction pathway and better understand the reaction mechanism, a control reaction of benzothiazolone with Et₂SiH₂ was performed in the presence of DBN under the same other conditions, and no benzothiazole was detectable. This indicated that benzothiazolone was not an intermediate for the formation of benzothiazole. ¹H NMR analysis was employed to identify the possible intermediates formed during the reaction process. As illustrated in Fig. 2, a new signal appeared at δ = 8.12 ppm when Et₂SiH₂ reacted with CO₂ in the presence of DBN comparing with ¹H NMR spectra of pure Et₂SiH₂ and DBN. This signal was ascribed to silyl formate produced from the reaction of Et₂SiH₂ with CO₂, suggesting that it was an intermediate for the synthesis of benzothiazole. It was reported that formylation reaction could accessibly proceed between amines and silyl formate due to the relatively low Gibbs free energy confirmed by the theoretic calculations.^16a

Fig. 2 ¹H NMR spectra of: (a) pure Et₂SiH₂; (b) pure DBN; (c) reaction solution from Et₂SiH₂ reacted with CO₂ in the presence of DBN. Reaction condition: DBN, 1 mmol; Et₂SiH₂, 1.5 equiv.; CO₂, 5 MPa; 150 °C; 24 h. 0.5 mL of DMSO-d₆ solution of the reaction solution was transferred into the NMR tube.

Based on the experimental results and the previous reports,^16a,24 a possible reaction pathway was proposed, as illustrated in Scheme 2. Firstly, silyl formate was formed via the reaction of Et₂SiH₂ with CO₂ catalyzed by DBN, which was the key step for the synthesis of benzothiazole. Then the nucleophilic NH₂ group in 2-aminothiophenol would easily attack the silyl formate, leading to the formation of the formamide intermediate 1. Subsequently, intermediate 2 was obtained through the intramolecular nucleophilic attack of SH group to the carbon atom of intermediate 1. Finally, the dehydration reaction of intermediate 2 took place, producing benzothiazole. It was worth noticing that the byproduct benzothiazolone was inevitably formed due to the competitive side reaction of 2-aminothiophenol and CO₂ under the experimental conditions.

Scheme 2 Possible reaction pathway.

Conclusions

In summary, we have demonstrated a new route to synthesize benzothiazoles via the cyclization of 2-aminothiophenols by CO₂ in the presence of Et₂SiH₂ catalyzed by DBN. Hydrosilane played an important role in the formation of benzothiazoles, and suppressed the production of benzothiazolones as the byproducts. This strategy provides an environmental benign approach for the synthesis of benzothiazoles and achieves the construction of C–S chemical bond using CO₂ as C1 building block. Further investigation on reducing the amounts of hydrosilanes for the synthesis of benzothiazoles is in progress in our laboratory.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (no. 21125314, 21321063) and Chinese Academy of Sciences.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Materials, experimental details, and characterization. See DOI: 10.1039/c4ra09372k

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