Electrochemical synthesis of selenyl imidazo[2,1-b]thiazinones via three-component reactions

Abstract

An efficient, green and one-pot strategy for the concise synthesis of diverse selenyl imidazo[2,1-b]thiazinones from diselenides, acryloyl chlorides and 2-mercaptobenzimidazoles/2-mercaptoimidazoles via electrochemical oxidative three-component tandem reactions in the absence of transition metals and oxidants has been developed. The electrochemical method has the advantages of good functional group tolerance, readily available raw materials, high step economy, and mild reaction conditions. Mechanistic studies indicated that selenium cations formed via direct electrochemical oxidation of diselenides may be involved as important intermediates in this process.

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Introduction

Nitrogen- and sulfur-containing heterocycles are prevalent in a diverse array of natural products and small-molecule pharmaceuticals.¹ Among them, compounds featuring the imidazo[2,1-b]thiazinone skeleton occupy a prominent position in the realm of medicine due to their superior biological activities such as tuberculostatic activity,^2,4 antiviral activity,³ antitumor activity⁵ and more⁶ (Scheme 1). Therefore, imidazo[2,1-b]thiazinone derivatives have attracted significant attention from organic chemists, and some excellent approaches have been discovered in recent years for the preparation of such compounds.⁷ Traditionally, the synthesis of imidazo[2,1-b]thiazinone skeletons was achieved by the cyclization reaction of 2-mercaptobenzimidazoles with 2-halobenzoyl chlorides,⁸o-iodobenzoic acids,⁹ or benzamides with a directing group¹⁰ under heating and transition-metal-catalyzed conditions (Scheme 2a–c). Alternatively, such compounds could also be synthesized at room temperature using an expensive NHC catalyst from 2-mercaptobenzimidazoles and alkynyl acids (Scheme 2d). Although these known methods are generally efficient, there are still some limitations, such as the requirement of transition metals, high temperature, pre-functionalized raw materials, or expensive NHC, which confine their applications. Therefore, the development of gentle and facile methods for synthesizing imidazo[2,1-b]thiazinones from simple starting materials under transition metal- and oxidant-free conditions is highly desirable.

Scheme 1 Bioactive molecules containing an imidazo[2,1-b]thiazinone skeleton.

Scheme 2 Strategies related to the construction of imidazo[2,1-b]thiazinones.

Organoselenium compounds are widely present in the fields of natural products, pharmaceuticals, agrochemicals, and functional materials and have received widespread attention from synthetic organic chemists and medicinal chemists.¹¹ Therefore, the synthesis of organoselenium compounds,¹² especially the construction of C–Se bonds,¹³ has become a research hotspot in recent years. In this context, various selenium reagents are used to introduce selenium atoms into organic molecules, such as diselenides, PhSeBr, PhSeCl, PhthSe and selenium powder. Among them, diselenides have become one of the most popular selenium reagents for constructing C–Se bonds owing to their stability, easy availability, and convenient operation. Recently, electrochemical synthesis¹⁴ has been widely used in organic transformations as a green and powerful synthesis method, due to its ability to efficiently generate active intermediates under environmentally friendly and sustainable conditions. This strategy to prepare organoselenium compounds has become a highly favored choice for synthesizers, and a series of excellent achievements have been made.¹⁵ Given the importance of organoselenium compounds and imidazo[2,1-b]thiazinones, as well as our sustained focus on 2-mercaptobenzimidazoles¹⁶ and electrochemical synthesis,¹⁷ herein we report a new three-component cascade reaction for the synthesis of selenyl imidazo[2,1-b]thiazinones from diselenides, acryloyl chlorides and 2-mercaptobenzimidazoles/2-mercaptoimidazoles under electrochemical conditions, avoiding the use of transition metals and oxidants (Scheme 2e).

Results and discussion

At the outset, we selected diphenyl diselenide (1a), methacryloyl chloride (2a), and 2-mercaptobenzimidazole (3a) as the model substrates to investigate the ideal reaction conditions for the electrochemical preparation of 3-methyl-3-(phenylselanyl)-2,3-dihydro-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-one (4a). To our delight, the target compound 4a was obtained in 90% isolated yield when the model reaction was performed in an undivided electrolytic cell with Cs₂CO₃ (0.1 mmol) as the base, tetrabutylphosphonium bromide (TBPB, 0.2 mmol) as the electrolyte, MeCN (4 mL) as the solvent and carbon plates as electrodes under a constant current of 3 mA at room temperature for 4 h (Table 1, entry 1). The subsequent control experiments clearly demonstrated that the reaction was an electrochemical synthesis reaction, and the electrolyte and base were crucial for the reaction (Table 1, entries 2–4). Next, other solvents were also examined, including MeOH, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP), but the yields were very poor (Table 1, entries 5–8). Screening of electrolytes showed that tetrabutylammonium iodide (TBAI), tetrabutylammonium hexafluorophosphate (TBAPF₆), or tetrabutylammonium acetate (TBAOAc) led to decreased yields (Table 1, entries 9–11). Other bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), t-BuOK, and pyridine, led to lower yields or inhibited the reaction (Table 1, entries 12–14). When the amount of Cs₂CO₃ was increased or decreased, only compound 4a could be obtained in 85% and 73% yields, respectively (Table 1, entry 15). Thereafter, we explored the effects of current and time on the reaction results and found that increasing or decreasing the current and prolonging or shortening the time did not further improve the reaction efficiency (Table 1, entries 16 and 17). Finally, we investigated the effect of electrode materials on the reaction and found that the carbon anode and carbon cathode were the best choice (Table 1, entries 18–20).

Table 1 Optimization of reaction conditions^a

Entry	Variation from the standard conditions	Yield (%)
a Reaction conditions: 1a (0.05 mmol), 2a (0.4 mmol), 3a (0.2 mmol), TBPB (0.2 mmol), Cs2CO3 (0.1 mmol), MeCN (4 mL), C plate (15 mm × 10 mm × 1 mm) cathode, C plate (15 mm × 10 mm × 1 mm) anode, undivided cell, current = 3 mA, room temperature, air and 4 h. Isolated yields. N.D. = not detected.
1	None	90
2	No electricity	N.D.
3	No TBPB	42
4	No Cs2CO3	38
5	MeOH instead of MeCN	Trace
6	DMF instead of MeCN	30
7	DMSO instead of MeCN	Trace
8	NMP instead of MeCN	N.D.
9	TBAI instead of TBPB	67
10	TBAPF6 instead of TBPB	81
11	TBAOAc instead of TBPB	73
12	DBU instead of Cs2CO3	57
13	t-BuOK instead of Cs2CO3	68
14	Pyridine instead of Cs2CO3	44
15	0.15 mmol or 0.08 mmol of Cs2CO3 instead of 0.1 mmol of Cs2CO3	85/73
16	3 or 5 h instead of 4 h	70/83
17	2 or 4 mA instead of 3 mA	80/88
18	C (+)|Ni (−) instead of C (+)|C (−)	69
19	Pt (+)|Pt (−) instead of C (+)|C (−)	82
20	Ni (+)|Pt (−) instead of C (+)|C (−)	Trace

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After determining the optimal reaction conditions, we further explored the substrate range of diselenides (1) with 2a and 3a to verify the practicality and universality of the electrochemical strategy, as shown in Scheme 3. Generally, diphenyl diselenides with either an electron donating group or an electron withdrawing group on the benzene ring could be converted into the target products 4b–4m in 46–95% yields. It was evident that this reaction was almost unaffected by the electronic effect; however, steric hindrance played an important role in the process. It is worth mentioning that strong electron withdrawing groups such as trifluoromethyl, cyano, and nitro could be tolerated, and the corresponding products 4n, 4o, and 4p could be obtained with yields of 84%, 57%, and 36%, respectively. Diphenyl diselenides with two substituents attached to the benzene ring could also be efficiently transformed into selenyl imidazo[2,1-b]thiazinones (4q–4s, 63–72%). The reaction was also compatible with diheteroaryl diselenides such as di(thiophen-2yl)diselane, providing the corresponding product 4t in 85% yield. In order to further prove the generality of the method, we also investigated the reactivity of 1,2-di(naphthalen-2-yl)diselane, 1,2-dibenzyldiselane, and 1,2-dimethyldiselane and found that the appropriate products 4u–4w could still be obtained in 80–83% yields.

Scheme 3 Substrate scope of diselenides. Reaction conditions: 1 (0.05 mmol), 2a (0.4 mmol), 3a (0.2 mmol), TBPB (0.2 mmol), Cs₂CO₃ (0.1 mmol), MeCN (4 mL), C plate (15 mm × 10 mm × 1 mm) cathode, C plate (15 mm × 10 mm × 1 mm) anode, undivided cell, current = 3 mA, room temperature, air and 4 h. Isolated yields.

Encouraged by the above results, the scopes of acryloyl chlorides (2) and 2-mercaptobenzimidazoles/2-mercaptoimidazoles (3) were explored subsequently (Scheme 4). When acryloyl chloride reacted with diphenyl diselenide (1a) and 2-mercaptobenzimidazole (3a) under the optimal conditions, product 5a was obtained in 20% yield. Thereafter, the nature of 2-mercaptobenzimidazoles was investigated to further demonstrate the versatility of the system. 2-Mercaptobenzimidazoles with an electron-donating (Me) or electron-withdrawing (Br) group at the 5 position reacted successfully, and the corresponding products 5b + 5b′ and 5c + 5c′ could be obtained with yields of 69% and 80%, respectively. To our delight, 2-mercaptobenzimidazoles with electron-rich (Me) or electron-deficient (F and Cl) groups at the 5 and 6 positions could successfully afford the desired products with moderate to good yields (5d–5f, 67–87%). Furthermore, 2-mercaptoimidazole and 4,5-diphenyl-1H-imidazole-2-thiol were also converted into selenium containing products 5g and 5h with yields of 48% and 40%, respectively.

Scheme 4 Substrate scope of 2-mercaptoimidazoles and enoyl chlorides. Reaction conditions: 1a (0.05 mmol), 2 (0.4 mmol), 3 (0.2 mmol), TBPB (0.2 mmol), Cs₂CO₃ (0.1 mmol), MeCN (4 mL), C plate (15 mm × 10 mm × 1 mm) cathode, C plate (15 mm × 10 mm × 1 mm) anode, undivided cell, current = 3 mA, room temperature, air and 4 h. Isolated yields.

Additionally, this three-component tandem reaction could be readily scaled up to the gram scale. Under slightly adjusted conditions, 1a (0.78 g, 2.5 mmol) reacted with 2a (2.1 mL, 20 mmol) and 3a (1.5 g, 10 mmol), affording the desired product 4a in 70% yield after 12 hours (Scheme 5). This outcome to some extent indicated the potential applicability of the method.

Scheme 5 Gram-scale reaction. Reaction conditions: 1a (2.5 mmol), 2a (20.0 mmol), 3a (10.0 mmol), TBPB (10.0 mmol), Cs₂CO₃ (5.0 mmol), MeCN (50 mL), C plate (30 mm × 20 mm × 1 mm) cathode, C plate (30 mm × 20 mm × 1 mm) anode, undivided cell, current = 10 mA, room temperature, air and 12 h. Isolated yields.

To investigate the possible reaction mechanism of this reaction, a series of control experiments were systematically conducted (Scheme 6). First, the radical nature of this reaction was studied through radical trapping experiments. Clearly, under standard conditions, when a radical scavenger such as 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT), or 1,1-diphenylethene (DPE) was added to the reaction mixture, the reaction could proceed smoothly, with only a slight decrease in the yield. Therefore, we speculated that the main reaction pathway of this reaction was not the radical pathway, but an ionic reaction process. Based on previous reports,^17a selenium cations may be formed via direct electrochemical oxidation of diselenides in the transformation. To substantiate this conjecture, the reaction was replicated without electricity using phenyl selenium chloride in lieu of diphenyl diselenide (Scheme 6b), resulting in product 4a with 80% yield. This reaction result supports the formation of anionic intermediates during the reaction process. The cyclic voltammetry (CV) experimental results revealed that upon addition of 1a, a distinct oxidation peak was observed at 1.327 V, indicating the facile oxidation of 1a under these conditions (Fig. 1). Next, a deuterium labeling experiment was conducted (Scheme 6c) using D₂O as the electrophilic reagent in place of diphenyldiselenide, under standard conditions, yielding the corresponding deuterated product (6-d).

Scheme 6 Control experiments.

Fig. 1 Cyclic voltammetry experiments. Cyclic voltammograms were recorded using a CHI660E electrochemical workstation at room temperature. A glassy carbon-disk (R = 5.5 mm, h = 10 mm) was used as the working electrode. A Pt disk (R = 5.5 mm, h = 10 mm) and Ag/AgCl (R = 5.0 mm, h = 10 mm) were used as the counter and reference electrodes, respectively. The scan rate was 100 mV s⁻¹.

Based on our mechanistic probe experiments and literature reports,^17a a plausible mechanism for this electrochemical oxidative three-component tandem reaction is proposed. As shown in Scheme 7, diselenide 1a is first oxidized at the anode to form the cationic radical intermediate A, which dissociates into selenium cation B and selenium radical C. Subsequently, 1a is regenerated by auto-coupling of radical C. In the presence of a base, the reaction of compound 2a and 3a leads to the formation of intermediate D. Thereafter, the intramolecular cyclization reaction of intermediate D produces intermediate E. Finally, intermediate E is captured by the cationic species C to form the target product 4a.

Scheme 7 Plausible mechanism.

Conclusions

In summary, we have developed an environmentally friendly synthesis approach for selenyl imidazo[2,1-b]thiazinones using readily available diselenides, acryloyl chlorides, and 2-mercaptobenzimidazoles. This method does not require the addition of oxidants or transition metal catalysts. It has the advantages of good functional group tolerance, simple reaction conditions, and high step economy. Mechanistic studies indicate that the carbanion and selenium cation are significant intermediates in the reaction process.

Author contributions

C. Liu conceived and oversaw the project. Y. Yue and Z. Chen performed the experimental work. B. Wang performed the NMR studies. Y. Yue and Z. Chen jointly wrote the manuscript. F. Xue, S. Wu, Y. Xia, Z. Chen and Y. Zhang provided useful advice. All authors discussed the results and reviewed the manuscript.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was supported by the Tianshan Talents Program for Leading Talents in Science and Technology Innovation (No. 2022TSYCLJ0016), the Key Program of Natural Science Foundation of Xinjiang Uygur Autonomous Region (2022D01D06), the National Natural Science Foundation of China (Grant No. 22361044, 21961037, and 22201241) and the Tianchi Talents Introduction Program (No. 5105240151a).

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2321470. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01354a

‡ These authors contributed equally to this work.

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