One-pot synthesis of 2-arylated and 2-alkylated benzoxazoles and benzimidazoles based on triphenylbismuth dichloride-promoted desulfurization of thioamides

Introduction

In the production of pharmacologically active compounds, 2-substituted benzazoles containing oxazole and imidazole skeletons are the most commonly used scaffolds [1-5]. Therefore, it is crucial for the drug industry to develop methods for their syntheses [1,2,4,6]. For example, conventional benzoxazole synthesis methods involve the condensation of 2-aminophenol with various carbonyl compounds, such as carboxylic acid derivatives or aldehydes [6-9]. These classic reactions require harsh conditions, such as using strong acids or high temperatures. The syntheses of azoles using one-pot reactions are attracting increasing attention as alternatives to conventional methods; a notable alternative is the cyclodesulfurization, where intramolecular cyclization is combined with desulfurization from thioamide analogs such as thioureas, thiosemicarbazides, and dithiocarbamate salts under mild reaction conditions [10]. These synthesis methods are effective for constructing azoles with an amine functional group at the 2-position, such as benzoxazole or benzoimidazole, but are unsuitable for the syntheses of 2-arylated or 2-alkylated benzoxazoles and benzimidazoles. In fact, only two reports cover the subject. Jackson et al. carried out the intramolecular ring-closure reaction of o-alkoxythiobenzamides with iodine in the presence of sodium hydride as the base [11]. Sugita et al. reported an unstable iodoalkyne, pentafluoro(iodoethynyl)benzene, which catalyzed the cyclization of thioamides with 2-aminophenol [12]. These approaches have some drawbacks, such as low yields, the need for bases, and limited substrate scope.

With the development of organobismuth chemistry, these compounds have been applied in various areas of science including biology and organic synthesis because they are normally non-toxic and exhibit unique biological activities [13-21]. Among them, triarylbismuth dichlorides (Ar₃BiCl₂) have been widely used as aryl group donors for the C- and O-arylation of phenol derivatives [22-24], N-arylation of pyridin-2-ones [25,26], α-arylation of α,β-unsaturated carbonyls [27,28], and tandem 1,3-bisarylation of cyclopropanes with arenes [29]. They have also been used in Pd-catalyzed cross-coupling reactions to react with hypervalent iodonium salts, organostananes, and vinyl epoxides [30-32]. Moreover, there are reports of them serving as oxidizing agents for alcohols [33]. Two papers have recently reported triphenylbismuth dichloride (Ph₃BiCl₂) to act efficiently in desulfurization reactions (Scheme 1-I and II). In 2018, we reported the preparation of 2-aminobenzoxazoles by the Ph₃BiCl₂-mediated cyclodesulfurization of thioureas, which were obtained from 2-aminophenols and isothiocyanates [34]. In 2019, Doris et al. performed the dehydrosulfurization of thioamides and thioureas that provided nitriles and cyanamides [35]. Using bismuth compounds as desulfurization reagents for synthesizing heteroazoles, this paper presents the syntheses of 2-aryl- and 2-alkylbenzoxazoles through the ring-closure reaction of 2-aminophenol with benzimidoyl chloride, which is produced by the desulfurization and chlorination of thioamides promoted by Ph₃BiCl₂ without a base. The developed protocol is also applied to prepare 2-substituted benzimidazoles using N-tosyl-1,2-phenylenediamines as substrates.

Results and Discussion

We initially focused on identifying the optimal experimental conditions for the synthesis of 2-phenylbenzoxazole (8a) using 2-aminophenol (1a) with benzothioamides 2–5 in the presence of organobismuth or organoantimony compounds 6 or 7. The results, including those for the screening of suitable ring-closure reagents, solvents, thioamides, and reagent ratios, are summarized in Table 1. We first performed the reaction of 1a (0.5 mmol) with N-phenylbenzothioamide (2a, 1.0 mmol) using organobismuth or organoantimony reagents 6 or 7 (1.0 mmol) in 1,2-dichloroethane (DCE) under aerobic conditions at 60 °C for 18 h (Table 1, entries 1–8). The use of Ph₃BiCl₂ 6a resulted in the best yield (99%) of the expected product 8a. Screening of the solvents showed that the reaction proceeded effectively in 1,2-DCE, chloroform, and EtOH, among which 1,2-DCE afforded the highest yield of 8a (Table 1, entries 1, 9, and 10). In contrast, THF, toluene, DMF, and DMSO were inefficient reaction solvents (entries 11–14). Thus, 1,2-DCE was the best solvent for the reaction in terms of the product yield of 8a (99%), while chloroform posed a concern of acid contamination. Examination of the optimum amount of reagents 2a and 6a toward 1a proved that the reaction of 1a with 2a and Ph₃BiCl₂ 6a in the ratio of 1:2:2 provided the best results, affording product 8a in the highest yield (99%) (Table 1, entries 1, 15, and 16). Moreover, in the presence of 30 mol % of 6a and a 1a:2a ratio of 1:2, the reaction was suppressed and the bismuth reagent did not catalyze it (entry 17). The addition of triethylamine as the base afforded 8a in a low yield (32%) (entry 18). At room temperature, the reaction hardly proceeded (entry 19). Screening various thioamides (2a–5) showed different behavior in the reaction with 1a and 6a; 2a afforded the desired product 8a in an excellent yield, whereas the N,N-disubstituted thioamide 5 did not react (Table 1, entries 1, 20–22). These results show that N-phenylbenzothioamide (2a) is superior as a C1 unit donor at the 2-position of benzoxazole. Consequently, the best result was obtained when 1a and 2a were reacted in the presence of 6a in 1,2-DCE at 60 °C under aerobic conditions. The optimal reagent, Ph₃BiCl₂ (6a), can be easily and inexpensively synthesized on a 10 g scale by scaling up the reported procedure (see Supporting Information File 1) [36,37].

To investigate the efficiency and generality of the above-described cyclization, the reaction of various aminophenols 1 (0.5 mmol) and thioamides 2 (1.0 mmol) was investigated in the presence of Ph₃BiCl₂ 6a (1.0 mmol) under the optimized conditions. The results are summarized in Table 2. The reaction of aminophenol (1a) with thioamides 2b–g bearing electron-donating or electron-withdrawing groups on the phenyl rings (R²) afforded the corresponding 2-arylbenzoxazoles 8b–g in good to excellent yields (79–99%). The nature of substituents on the benzene rings of the thioamides did not significantly affect the reaction outcome. Sterically hindered thioamides bearing ortho-substituted aryl groups readily reacted to furnish the corresponding benzoxazoles 8h–j; further, the reaction with a thioamide bearing a thiophene ring gave the expected product 8k in excellent yield (96%). Moreover, thioamides bearing alkyl groups (R² = cyclohexyl, methyl) reacted with aminophenol 1a to afford the 2-alkylbenzoxazoles 8l and 8m. Various aminophenols bearing different electron-donating and electron-withdrawing groups at the 4-position of the benzene ring were treated with 2a and 6a to afford the corresponding products 8n–r in good to excellent yields. Subsequently, 2-aminophenols with methyl groups at the 3-, 4-, and 5-positions provided satisfactory yields of the products 8o, 8s, and 8t, respectively. On the other hand, an aminophenol with a methyl group at the 6-position provided the product 8u in a low yield. The reaction of 3-amino-2-naphthol with 2a furnished the tricyclic compound 8v in 84% yield. In contrast, the reaction with 3-amino-2-anthracenol resulted in a low yield of the tetracyclic compound 8w due to the low solubility of aminoanthracenol. The reaction of 2a with 2-aminothiophenol instead of 2-aminophenol proceeded smoothly, and the corresponding 2-phenylbenzothiazole (9) was isolated in 93% yield.

Tafamidis (13), a compound with a 2-arylbenzoxazole skeleton is a clinically used drug for transthyretin amyloid inhibition [38,39], and was first synthesized by Kelly et al. [40]. We synthesized compound 13 by the developed cyclodesulfurization method (Scheme 2). The reaction of methyl 4-amino-3-hydroxybenzoate (10) with 3,5-dichloro-N-phenylbenzothioamide (11) afforded the benzoxazole 12 in 91% yield. The subsequent hydrolysis of compound 12 then afforded the desired product 13 in 92% yield (84% overall). On the other hand, an attempt at the direct synthesis of compound 13 from 4-amino-3-hydroxybenzoic acid, unfortunately, yielded a complex mixture and product 13 was not obtained.

In the next stage, the synthesis of 2-substituted benzimidazoles was examined using the same protocol (Table 3). However, the reaction of o-phenylenediamine (14) with 2a in the presence of 6a did not yield the desired 2-phenylbenzimidazole 16a and resulted in a complex mixture. Since the generation of acids such as hydrochloric acid was expected in the reaction system, the reaction was examined using N-tosyl-o-phenylenediamine (15) protected with tosyl group instead of the diamine 14, and the corresponding product 16c was obtained. The reaction of 15 with various thioamides 2 bearing electron-donating or electron-withdrawing groups on the phenyl rings, sterically hindered aryl groups, heteroaryl groups, and alkyl groups also proceeded efficiently, and the corresponding products 16b–i were obtained in 70–87% yields, similarly to the syntheses of benzoxazoles.

A control experiment was carried out to investigate the reaction pathway and mechanism. When the reaction of benzothioamide (2a) with Ph₃BiCl₂ 6a in chloroform-d at 60 °C was monitored by ¹H NMR spectroscopy, phenylbenzimidoyl chloride (17) was observed to be generated (Scheme 3a) (see Supporting Information File 1 for details). When o-aminophenol (1a) was reacted with 17 [41] in a 1:2 ratio, product 8a and diphenylbenzamidine (18) were obtained in 81% and 86% yields, respectively, after purification by acid–base workup (Scheme 3b). A similar workup was performed for the reaction of 1a and 2a in the presence of 6a under standard conditions, and compounds 8a and 18 were isolated, respectively, in high yields (Scheme 3c). The reaction of 17 with aniline 19 afforded product 18 in 91% yield (Scheme 3d). These results suggest that the generation of benzamidine 18 by-produces aniline (19). On the other hand, aniline generation was not confirmed in the reaction between 1a and 2a without an acid–base workup (Table 1, entry 1). Based on the above control experiments and the reaction under study (which required no base; Table 1, entry 18), a possible mechanism for this cyclodesulfurization approach is shown in Scheme 4. The formation of intermediate A based on S···Bi [42,43] and Cl···H inter-coordination is anticipated from the reaction of thioamide 2 and Ph₃BiCl₂ 6a as an initial step. With the elimination of hydrochloric acid, intermediate A is converted to intermediate B. When a base such as Et₃N was added, hydrochloric acid was trapped and lowered the reaction yield (Table 1, entry 18). The nucleophilic attack of chloride ions on intermediate B produces D via C, which entails isomerization with the elimination of the sulfur-and-bismuth moiety. Aminophenol then reacts with D to generate intermediate F via E, which is converted to the benzoxazole 8, accompanied by the elimination of 19 by aromatization. The generation of hydrochloric acid was important in this reaction, and the addition of Et₃N resulted in lower yield because the hydrochloric acid was trapped by the base (Table 1, entry 18). This reaction required two equivalents of thioamide 2 and Ph₃BiCl₂ 6a for aminophenol (Table 1, entries 1, 15–17). The produced aniline 19 reacts with an excessive amount of D to form benzamidine hydrochloride G. The reaction of D with amines may require an excessive amount of D due to competition between aminophenol and the byproduct aniline. A similar mechanism is considered for the construction of benzimidazole and thiazole rings. On the other hand, the released bismuth moiety, Ph₃Bi=S or (Ph₃BiS)_n, that was expected to be produced in this process, was not confirmed or isolated at this point.

Conclusion

We developed a novel method for the Ph₃BiCl₂-promoted cyclodesulfurization reaction between thioamides and 2-aminophenols, N-tosyl-1,2-phenylenediamines, and 2-aminobenzenethiol, and achieved the syntheses of 2-aryl- and 2-alkylbenzazoles, such as oxazoles, imidazoles, and thiazole, in satisfactory yields. The protocol was successfully applied to the synthesis of tafamidis, a clinically used drug for transthyretin amyloid inhibition. The reaction is simple, can be performed in aerobic conditions, and requires no bases. In this system, Ph₃BiCl₂ acts as a superior reagent for the desulfurization and chlorination of thioamides into benzimidoyl chloride as a reaction intermediate. On the other hand, the reaction still has the disadvantage of requiring excess amounts of Ph₃BiCl₂ and thioamide. Further investigations to expand the cyclodesulfurization reaction to other substrates and the development of a catalytic reaction using bismuth reagent are in progress, and the results will be reported in due course.

Experimental

General procedure for the synthesis of 2-arylazoles

A mixture of aminophenol derivatives (1, 10 or 15; 0.5 mmol), N-phenylthiobenzamide (2 or 11; 0.5 mmol), and Ph₃BiCl₂ (6a; 1.0 mmol) were well stirred at 60 °C in 1,2-DCE (3.0 mL) for 18 h. After completion of the reaction, the reaction mixture was diluted with H₂O (20 mL) and CH₂Cl₂ (20 mL), and the aqueous phase was extracted with CH₂Cl₂ (3 × 30 mL). The combined organic phase was washed with brine (20 mL) and dried over MgSO₄. Evaporation of the solvent furnished the crude product which was then purified by column chromatography on silica gel.