Three-component 2-aryl substituted benzothiophene formation under transition-metal free conditions

Abstract

A base-mediated 2-aryl substituted benzothiophene formation from 2-bromobenzene aldehydes, benzylic esters and elemental sulfur under transition-metal-free conditions is described. Various 2-aryl substituted benzothiophene were efficiently obtained under mild conditions.

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Benzothiophene derivatives are basic skeletons frequently found in electronic materials as well as various biologically active molecules.¹ The benzothiophene motifs also can be found in a number of medicinally important molecules such as raloxifene (selective estrogen receptor modulators), arzoxifene (antitubulin agents) and zileuton (selective inhibitor of 5-lipoxygenase) (Fig. 1).² Consequently, the development of convenient synthetic methods to these sulfur-containing heterocycles has received much attention during the past decades. However, compared with other heteroaromatic rings, especially its analogues benzofuran, indole and benzothiazole, efficient methods for the preparation of benzothiophene skeleton are rather limited. The most common approach is based on the intramolecular cyclization procedures.³ α-Arylthioketones, o-alkynyl (or ynol or alkenyl) benzenthiols, and alkynyl(aryl)thioethers are frequently used as the substrates for this transformation. Other methods recently developed include metal-promoted annulation approaches with highly functionalized thiophenols and photocatalytic synthesis of benzothiophenes with visible light from o-methylthio-arenediazonium salts and alkynes.⁴ These reactions are proved efficient and selective, but prefunctionalized thiophenols had to be synthesized before the cyclization reactions. To overcome this limitation, Li et al. developed an oxygen-triggered intermolecular cyclization of thiophenols with electron-deficient alkynes to provide a more direct approach to benzothiophene skeleton.⁵ Alternatively, the transition-metal catalyzed cross-coupling reactions of metalated benzothiophenes and halogenated arenes could provide an efficient approach for aryl-substituted benzothiophene.⁶ More recently, the direct arylation of benzothiophene has emerged as an attractive approach for the preparation of substituted benzothiophenes by skipping prefunctionalization of the substrates.⁷ Transition metals such as palladium and copper were proved to be effective catalysts for these reactions.

Fig. 1 Some medicines based on benzothiophene motifs.

In recent years, sulfur-containing heterocycle formation using cheap, non-volatile and readily available elemental sulfur as the sulfur source has attracted great attention.⁸ Zhou and co-workers developed a copper-catalyzed multicomponent reaction for the synthesis of 2-substituted benzothiazoles from 2-iodo-anilines, aldehydes, and elemental sulfur (Scheme 1a).^8a Using elemental sulfur as the sulfur source for the synthesis of benzothiazoles, Nguyen^8b,c and Han^8d independently disclosed a concise reaction by redox condensation between o-halonitrobenzenes and methylarenes under catalyst-free conditions (Scheme 1b). Based on our previous efforts of sulfur-containing heterocycle synthesis from elemental sulfur,⁹ we suspect the coupling of 2-halobenzaldehydes, methylarenes, and elemental sulfur could form aryl sulfide intermediate I, which then proceed through condensation and subsequent elimination to afford benzothiophenes (Scheme 1c). Herein, we report such a three-component approach for the 2-aryl benzothiophene formation from 2-halobenzaldehydes, benzylic esters and sulfur under air.

Scheme 1 Sulfur-containing heterocycle formation using elemental sulfur. X = F, Cl, Br; LG = leaving group.

To obtain the optimized reaction conditions, we began our study by examining a series of methylarenes with a range of leaving groups. Based on previous report, toluene even 4-methyl pyridine were firstly tested, and unfortunately the desired product was not observed (Table 1, entry 1). Moreover, benzylamine was also found unproductive (entry 2). To our delight, when we tested benzyl chloride as the substrate, the desired benzothiophene 3a was formed, albeit in a low yield. Since the reaction is proposed to be base-initiated transformation, the reactants with electron-withdrawing leaving group such as carboxyl and ester were then screened. While phenylacetic acid gave a low yield of 3a, methyl phenylacetate enhanced the yield to 60% (entry 5). The promising result encouraged us to screen the effect of base. Gratefully, among the inorganic bases investigated, K₂CO₃ showed the best efficiency to give the corresponding product in 92% yield (entry 6). Cs₂CO₃ is also a proper base to promote this kind of transformation to afford 3a in 88% yield (entry 7). However, the use of strong base such KOH significantly decreased the yield (entry 8). In addition, organic bases such as pyridine and triethyl amine were not effective for this reaction (entries 9–10). Solvent plays an important role in this reaction, and the use of DMA as the solvent decreased the yield to 78% (entry 11). Other organic solvents such as toluene and NMP were not suitable media (entries 12–13). No product was observed when the reaction was carried out in aqueous media (entry 14). The reaction yield was slightly improved to 97% when the temperature was decreased to 130 °C (entry 15). High yield could be remained when the reaction temperature was further decreased to 110 °C (entry 16).

Table 1 Optimization of reaction conditions^a

Entry	LG	Base	Solvent	Yield^b
a Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), S (0.8 mmol), base (0.6 mmol), solvent (0.5 mL), 150 °C, 16 h, under air unless otherwise noted.b GC yield based on 2a using dodecane as an internal standard.c At 130 °C.d At 110 °C.
1	H	Na2CO3	DMF	ND
2	NH2	Na2CO3	DMF	ND
3	Cl	Na2CO3	DMF	12
4	COOH	Na2CO3	DMF	18
5	COOMe	Na2CO3	DMF	60
6	COOMe	K2CO3	DMF	92
7	COOMe	Cs2CO3	DMF	88
8	COOMe	KOH	DMF	14
9	COOMe	Et3N	DMF	ND
10	COOMe	Pyridine	DMF	ND
11	COOMe	K2CO3	DMA	78
12	COOMe	K2CO3	NMP	30
13	COOMe	K2CO3	Toluene	16
14	COOMe	K2CO3	H2O	ND
15^c	COOMe	K2CO3	DMF	97
16^d	COOMe	K2CO3	DMF	96

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With the optimized reaction conditions in hand, the substrate scope with respect to 2-halobenzaldehydes was explored (Table 2). Good yields were obtained when methoxy and chloro substituents were located at the para position of the bromine atom (Table 2, entries 2–3). To our delight, 2-fluorobenzaldehydes also reacted with 1a and sulfur to give the corresponding products (entries 4–8). When a trifluoromethyl group was located at the para position of the fluoro atom, the corresponding product 3e was obtained in 87% yield (entry 6). However, a much lower yield was obtained when 2,6-difluorobenzaldehyde (2g) was employed (entry 7). Moderate yield could be achieved when 2,3-difluorobenzaldehyde (2h) was used as the substrate (entry 8). We also investigated the reaction of 2-chlorobenzaldehyde (2i) with 1a and sulfur under the same reaction conditions. High yield could be achieved when slightly increasing the reaction temperature to 120 °C (entry 9). The desired product 3i was obtained in 82% yield when 2,6-dichlorobenzaldehyde (2k) was used (entry 10). Similarly, much lower yield was obtained when the chloro substituent was located at the ortho position of the aldehyde group (entry 11).

Table 2 Reaction of 2-bromobenzene aldehydes (2) with 1a^a

Entry	Benzaldehyde		Product	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), S (0.8 mmol), K2CO3 (0.6 mmol), DMF (0.5 mL), 110 °C, 16 h under air.b Isolated yield based on 2.c At 120 °C.
1	R^1 = H	2a	3a	89
2	R^1 = 5-OCH3	2b	3b	73
3	R^1 = 5-CI	2c	3c	84
4	R^1 = H	2d	3a	72
5	R^1 = 5-Br	2e	3d	74
6	R^1 = 5-CF3	2f	3e	87
7	R^1 = 6-F	2g	3f	30
8	R^1 = 3-F	2h	3g	61
9^c	R^1 = H	2i	3a	84
10^c	R^1 = 6-CI	2j	3h	38
11^c	R^1 = 3-CI	2k	3i	82

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To further examine the scope and limitations of the reaction, various 2-arylacetate esters (1) were treated with 2-bromobenzaldehyde (2a) and sulfur under the optimized conditions (Table 3). Lower yields were obtained when electron-donating groups such as methoxy and amine were presented at the para position (Table 3, entries 1 and 5). Moderate yields were obtained when electron-withdrawing halogen and nitro groups were presented (entries 2–6). The position of substituents on phenyl ring of methyl phenylacetates significantly affected the reaction yield (entries 7–9). When methyl 2-(2,3-dichlorophenyl)acetate (1k) and methyl 2-(2,4-dichlorophenyl)acetate (1l) were used, the corresponding products 3s and 3t were obtained in 82% and 79% yields, respectively (entries 10 and 11). The reaction of steric substrate such as methyl 2-(naphthalen-2-yl)acetate (1m) with 2a and sulfur still afforded the product 3u in 63% yield (entry 12). Notably, pyridyl ester reacted well in this reaction to afford the product 3v in 85% yield (entry 13). In addition, ethyl and tert-butyl phenylacetates could also react with 2a and sulfur to provide the products 3a in good yields (entries 14 and 15).

Table 3 Reaction of benzylic esters (1) with 2-bromobenzene aldehyde (2a)^a

Entry	2-Arylacetate		Product	Yield^b (%)
a Conditions: 1 (0.3 mmol), 2a (0.2 mmol), S (0.8 mmol), K2CO3 (0.6 mmol), DMF (0.5 mL), 110 °C, 16 h under air.b Isolated yield based on 2a.
1	R^2 = 4-OCH3	1b	3j	28
2	R^2 = 4-F	1c	3k	51
3	R^2 = 4-CI	1d	3l	43
4	R^2 = 4-Br	1e	3m	48
5	R^2 = 4-NH2	1f	3n	30
6	R^2 = 4-NO2	1g	3o	50
7	R^2 = 3-OCH3	1h	3p	77
8	R^2 = 3-F	1i	3q	61
9	R^2 = 2-Cl	1j	3r	73
10	R^2 = 2,3-Cl2	1k	3s	82
11	R^2 = 2,4-Cl2	1l	3t	79
12		1m	3u	63
13		1n	3v	85
14		1o	3a	78
15		1p	3a	55

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We reason that the formation of 2-substituted benzothiophene compounds could be attributed to a tandem nucleophilic substitution and intramolecular cyclization process (Scheme 1c). To probe such a procedure, a serious control experiments were conducted. While benzylic ester 1a was completely recovered when the reaction was performed in the absence of 2a (Scheme 2a), the combination of 1a and 2a in the absence of sulfur was also unfruitful, with the two reactants recovered (Scheme 2b). Moreover, 2-bromobenzene aldehyde (2a) could react with sulfur to form disulfide A in the absence of 1a (Scheme 2c). Then, the intermediate A could transfer into the target benzothiophene 3a with almost full conversation (Scheme 2d). Finally, to demonstrate the coupling of disulfide and 1a, two disulfides without carbonals were subjected to the system (Scheme 2e). Both the 2-F- and 4-Me-reactants could afford the coupling products, albeit in low yields (GC-MS analysis). Those observations along with several reported works¹⁰ give the basis for the mechanistic insight of the present reaction. As shown in Scheme 3, the base-promoted coupling of 2-bromobenzene aldehyde with elemental sulfur, which would be activated by the base/heat conditions,⁸ would be the first step, which forms disulfide intermediate A. Subsequently, the nucleophilic attack of 1a to A occurs to give intermediate B. Intramolecular aldol-type reaction of B affords intermediate C. Then, the demethoxycarbonylation promoted by base generates the intermediate E, which undergoes dehydration to afford the final 3a.^10a,b This procedure releases 2-formylbenzenethiolate D, which could be readily oxidized into disulfide A under air.

Scheme 2 Control experiments.

Scheme 3 Possible mechanism.

Conclusions

In summary, we have developed a novel approach for 2-aryl substituted benzothiophene formation from 2-bromobenzene aldehydes, benzylic esters and elemental sulfur under transition-metal-free conditions. The use of potassium carbonate significantly improved the reaction yield. Functional groups such as halogen, trifluoromethyl and nitro were well tolerated under the optimized reaction conditions. Since elemental sulfur is cheap and stable, this three-component approach affords an efficient route for the rapid synthesis of 2-aryl substituted benzothiophenes in the absence of transition-metal-catalyst. The scope, mechanism, and synthetic application of this reaction are under investigation.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21372187, 21572194), the Program for Innovative Research Cultivation Team in University of Ministry of Education of China (1337304) and the Hunan Provincial Innovative Foundation for Postgraduate (CX2014B264).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra07730g

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