For this reason, the synthesis of this structure has attracted much attention in recent years. These methods can be broadly classified into two categories; (a) Arene with an ortho-alkynyl or alkenyl group activated by reactants produces benzothiophenes by intramolecular cyclization. b) Functionalized arene and alkyne react with each other to yield benzothiophenes via intermolecular reaction under transition metal catalysis or other suitable conditions. However, regardless of (a) or (b), most methods require additional additives, such as metal catalysts or oxidizers that produce unwanted chemical waste.
Here, we report a new synthetic method for benzothiophenes through electrosynthesis in the absence of oxidants and transition metals. Electrolysis of symmetric 2-alkenylaryl disulfides under undivided cells leads to the formation of the corresponding benzothiophenes in good to moderate yields. Unlike previous methods, which typically require the use of transition metal catalysts or chemical oxidants, our method provides a green approach to useful benzothiophenes.
Introduction
Electrochemical methods in organic synthesis
It promotes oxidation or reduction of the starting material in the presence of the desired nucleophile and reduces the possibility of peroxidation or overreduction of the resulting product by promoting electron transfer in a more selective and predictable manner. In the undivided cell, the anode and the cathode are not separated and are placed in the same chamber. This type is preferred because it is easy to set up the reaction, and since both reduction and oxidation occur within the same site, the substrate can be exposed to all species in the reaction.
In the split cell, the anode and cathode are physically separated into different chambers. There are two types of redox processes in the electrolytic process: One is direct electrolysis and the other is indirect electrolysis (Figure 4). First, in the case of direct electrolysis, the interaction between the electrode and the reactant occurs directly.
On the other hand, in the indirect methods, a redox catalyst, also called mediator, is used to transfer electrons from an electrode to the organic reactants. On the other hand, in constant voltage mode, the voltage flow is constant but the current is not constant.
Synthetic methods of benzothiophene
In the intramolecular method, the reaction is carried out using an arene with an ortho-alkenyl group instead of an alkynyl group. In 2017, Sekar developed the synthesis of 2-acylbenzothiophenes from 2-iodochalcones with α-C-H functionalization using a Cu catalyst and xanthate as a sulfur source13. The reaction undergoes an intra cyclization process that follows in situ sulfur incorporation to produce the desired product without an external acyl source.
This method is of greater importance in the synthesis of 1-(5-hydroxybenzothiophen-2-yl)ehtanone, which is known as a modulator of pre-mRNA splicing (Scheme 3). In the reaction mechanism, thiophenol is automatically oxidized and undergoes the following homologous cleavage process to yield thiyl radical. In 2014, Wang developed the n-Et4NBr-catalyzed synthesis of benzothiophenes via cascade reactions of disulfides and alkynes with S-S bond cleavage and alkenyl radical cyclization16.
During the reaction of tetraethylammonium bromide and peroxydisulfate, tetraethylammonium sulfate radical anions are formed, which react with disulfide and form a thiyl radical. In 2015, Yang developed an iodine-catalyzed method for the synthesis of benzothiophenes under metal- and solvent-free conditions by the reaction of substituted thiophenols and alkynes17. Meanwhile, as the halogenated product accumulates in solution, the dehalogenated product is obtained at the cathode (Scheme 8).
In 2021, Liu also developed the synthesis of sulfonated benzothiophenes under the condition that they are free of oxidants and catalysts20. In 2012, König and colleagues reported the visible light-mediated synthesis of benzothiophenes with aryldiazonium salts and alkynes in the presence of eosin Y photocatalyst. In the reaction mechanism, the aryl radical generated by SET is added to the alkyne and then cyclized to produce the sulphuranyl radical.
This radical is oxidized to a cation that transfers a methyl group to the nucleophile present in the reaction mixture by an SN2 process providing the final product (Scheme 11). Under these cost-effective and environmentally friendly reactions without transition metals, the KOH/DMSO system provides a facile and efficient synthesis of benzothiophenes ( Scheme 12 ). This reaction was carried out in the absence of transition metal catalysts and other additives.
In addition, even exposure to sunlight other than visible light can facilitate the reaction well. This method enables the synthesis of benzothiophenes with a variety of substituents, from good to moderate yields, under mild conditions.
Results and Discussion
- Substrate scope of benzothiophene
- Mechanistic studies
- Proposed reaction mechanism
- Substrate synthesis
Disulfide with an electron-withdrawing nitro group provided the corresponding benzothiophene in good yield (2e), as well as an electron-donating methoxy group (2f). Furthermore, substrates with amide groups ( 2g , 2h ), including the synthetically useful Weinreb amide ( 2h ), were successfully converted to the corresponding benzothiophenes. Although low yields were observed in the case of silyl protected alcohol (2 L) and free alcohol (2 m), the desired products were also obtained.
Cyclic voltammograms were recorded in an electrolyte solution of Et4NOTs (0.1 M) in anhydrous 1,2-dichloroethane (3 mL) with 0.1 mmol of substrate using a glassy carbon working electrode, a Pt wire counter electrode, and a 3 M KCl Ag. /AgCl reference electrode with scan rate 100 mV/s. It was confirmed that disulfide 1a is prone to oxidation by showing two oxidation potentials of 0.05 V and 1.30 V (vs. SCE). To confirm the reaction mechanism, the reaction was carried out with the addition of TEMPO or BHT under standard conditions.
After reviewing the previous work of EGA-catalyzed activation of diary disulfide to generate reactive ArS+ species, we hypothesized that EGA might participate during the course of the reaction. According to the previous report, the EGA-catalyzed reaction in an undivided cell should proceed well when the reaction substrate was added after electrolyzing the solvent-electrolyte system. In this regard, a 0.1 M solution of Et4NOTs in DCE was preelectrolyzed for 2.5 h under the standard reaction conditions.
It turned out that the reaction did not proceed and benzothiophene 2a was not found (Scheme 17). Although the isolated yield was reduced and an extended reaction time was required to completely consume 1a , the reaction was not completely inhibited and 2a was provided in a moderate yield of 45% ( Scheme 18 ). Finally, the radical intermediate E would undergo anodic oxidation and deprotonation to give the desired product 2a , while the cationic intermediate F would give the desired product 2a with subsequent deprotonation.
After the reaction of reduction and oxidation, a symmetrical 2-alkenyl aryl disulfide was synthesized using the Wittig reaction (Scheme 19). We then synthesized a disulfide bond from a t-butyl protected intermediate obtained by a substitution reaction from a bromide intermediate.
Conclusions
Experimental
The solution was stirred at 900 rpm for 1 minute at room temperature before turning on the power. The reaction mixture was transferred to the round bottom flask and the electrodes were washed several times with ethyl acetate which was combined in the same round bottom flask. When the reaction was determined to be complete by TLC, the mixture was cooled to 0 ℃ and water (1 ml), 15% aqueous NaOH (1 ml) and then water (3 ml) were carefully added.
The resulting aqueous phase is acidified with 1 N HCl solution to pH 2-3 and extracted three times with ethyl acetate. After stirring at room temperature, the mixture was passed through a plug of silica gel and rinsed with CH2Cl2 to afford the dialdehyde as a colorless solid. After completion of the reaction, water was added and the aqueous phase was extracted three times with ethyl acetate.
The reaction mixture was stirred at room temperature and quenched by the addition of water. After completion of the reaction, it was diluted with water and extracted three times with ethyl acetate. The crude material was purified by flash chromatography to afford 2-(tert-butylthio)-5-nitrobenzaldehyde as a yellow oil.
Once the reaction was determined to be complete by TLC, the mixture was poured into water and precipitates were collected and washed with water. The crude material was dried and purified by flash chromatography to give 6,6'-disulfaniylbis(3-nitrobenzaldehyde) as a yellow solid. The precipitate was collected by filtration, washed with water and dried under vacuum to give 2-bromo-5-methoxybenzaldehyde as a colorless solid.
After the evolution of H2 gas had stopped, 2-bromo-5-methoxybenzaldehyde (156 mg, 0.73 mmol, 1 equiv.) was added dropwise and the mixture was stirred at room temperature. Saturated aqueous NH4Cl was added and the mixture was extracted three times with ethyl acetate. The crude material was purified by flash chromatography to yield 2-(tert-butylthio)-5-methoxybenzaldehyde as a yellow oil.
The crude material was dried and purified by flash chromatography to yield 6,6'-disulfanediylbis(3-methoxybenzaldehyde) as a yellow oil.
Uneyama, Berlin, Heidelberg, 1987, The chemistry of electrogenerated acids (EGA); How to generate EGA and how to use it?
