One-step synthesis of benzo[b]thiophenes by aryne reaction with alkynyl sulfides

An aryne reaction with alkynyl sulfides affording benzo[b]thiophenes is disclosed. A wide range of 3-substituted benzothiophenes were synthesized from easily available o-silylaryl triflates and alkynyl sulfides in a one-step intermolecular manner. The synthesis of diverse multisubstituted benzothiophene derivatives involving a pentacyclic compound was achieved by virtue of the good functional group tolerance and versatile C2 functionalizations.


Introduction
Benzo [b]thiophenes are a promising class of organosulfur compounds. 1-3 In particular, multisubstituted benzothiophenes such as sertaconazole, raloxifene, and DNTT have served in a broad range of research elds including pharmaceutical sciences and materials chemistry (Fig. 1). In spite of their signicance, although a number of benzothiophene syntheses such as transition-metal catalyzed reactions have been developed, the synthesis of multisubstituted benzothiophenes remains still difficult in terms of the applicable functional groups and substitution patterns due to the limited methods constructing the benzothiophene skeleton and introducing substituents. 4,5 We herein present a novel approach to form benzothiophene scaffold from easily available alkynyl suldes and aryne precursors.
Reactions of aryne intermediates with a variety of suldes are attractive methods for preparing a wide range of organosulfur compounds (Fig. 2). [6][7][8][9] In the 1980s, a pioneering study on the reaction between suldes and benzyne intermediate (I) generated from benzenediazonium-2-carboxylate was reported by Nakayama and coworkers ( Fig. 2A). 9a,9b Recently, an elegant difunctionalization of aryne intermediates was achieved by Studer and coworkers, in which C-S and C-C formations and C-S cleavage simultaneously took place (Fig. 2B). 9h Benzothiophene synthesis from o-silylaryl triates and acyl-substituted ketene dithioacetals was developed by Singh and coworkers in 2016 through the formation of benzothiophene skeleton via aryne intermediates, and further addition with aryne intermediates (Fig. 2C). 9o On the basis of our recent studies of synthetic aryne chemistry, 10 we envisioned that benzothiophenes can be synthesized from aryne precursors and alkynyl suldes, 11,12 starting from the nucleophilic attack of the sulfur or carbon of alkynyl suldes to electrophilic aryne intermediates followed by ring-closure (Fig. 2D).

Results and discussion
First, a reaction between 2-chloro-6-(trimethylsilyl)phenyl tri-ate (1a) and ethyl p-tolylethynyl sulde (2a) was examined ( Fig. 3A and B). As a result, we found that treatment of a mixture  between aryne precursor 1a and alkynyl sulde 2a with cesium uoride in hot acetonitrile provided 3-(4-tolyl)-4-chlorobenzo [b] thiophene (3a) in high yield. The construction of benzothiophene scaffold was accomplished by C-S bond formation selectively at C1 of 3-chlorobenzyne (II), C-C bond formation, protonation, and deethylation, where the regioisomer was not detected. When the reaction was conducted on a larger scale using 2 mmol of alkynyl sulde 2a, the yield of benzothiophene 3a was slightly decreased. Increasing concentration from 0.05 M to 0.2 or 0.5 M slightly reduced the yield of 3a (64% or 52%, respectively). 13 Benzothiophene 3a was also obtained in moderate to good yields even when the amount of aryne precursor 1a was decreased from 3.0 equiv. to 2.0, 1.5, and 1.2 equiv. 13 These results show good practicality of the benzothiophene synthesis from o-silylaryl triates 1 and alkynyl suldes 2. The reaction of aryne precursor 1a with methyl, isopropyl, or benzyl p-tolylethynyl suldes instead of 2a also afforded benzothiophene 3a, although 3a was not detected in the case of ptolyl p-tolylethynyl sulde. 13 A broad range of 3-aryl-and 3-alkyl-substituted benzo [b] thiophenes were prepared from aryne precursor 1a and various alkynyl suldes 2 ( Fig. 3A and B). For example, electrondonating methoxy-and electron-withdrawing chloro-and methoxycarbonyl-substituted arylethynyl ethyl suldes smoothly reacted with aryne intermediates to afford benzo [b] thiophenes 3b-d without damaging these functional groups. Bulky 2-bromophenylethynyl ethyl sulde also participated in the reaction providing 3e in good yield. Furthermore, benzothiophenes 3f and 3g having p-extended aromatics and 3h possessing heteroaromatic thiophene ring were synthesized efficiently from the corresponding alkynyl suldes. The reaction of primary and secondary alkylethynyl ethyl suldes with aryne intermediates also proceeded under the same conditions to afford 3i and 3j in high yields. Moreover, we succeeded in the synthesis of benzothiophene 3k from alkynyl sulde 2k prepared from an ethynylestradiol derivative. Since a wide variety of alkynyl suldes were easily available from the corresponding terminal alkynes and thiosulfonates catalyzed by copper as we recently reported, 12e this method enables the synthesis of diverse 3-substituted benzothiophenes.
Diverse aryne precursors were applicable to the one-step benzothiophene synthesis enabling to prepare a variety of benzothiophenes 3l-v ( Fig. 3A and C). Not only simple benzyne but also 3-uoro-, 3-bromo, 3-methoxy, and 3-aminobenzyne intermediates reacted with alkynyl suldes 2a to furnish 3l-p in moderate to good yields leaving these functional groups untouched, in which regioisomers were not detected. Especially, selective C-S bond formation proceeded in the reaction of aryne intermediates bearing functional groups at 3-position, showing that the benzothiophene formation triggered by the nucleophilic attack of the sulfur atom onto C1 of the 3substituted aryne intermediates due to the inductive effect of uorine, bromine, oxygen, and nitrogen. 14 Reactions of 4methoxy-and 4-methylbenzyne with alkynyl sulde 2a furnished ca. 1 : 1 mixtures of regioisomers of benzothiophenes 3q and 3r in moderate to high yields. Trisubstituted benzothiophenes 3s and 3t were also synthesized from the corresponding o-silylaryl triates. It is worthy to note that the synthesis of pconjugated benzothiophenes 3u and 3v was accomplished from the corresponding benzothiophene-and phenanthrene-type osilylaryl triates. 10c The broad scope of the synthesizable benzothiophenes clearly demonstrated a benet of this method by virtue of the recent remarkable advancement of the accessibility of o-silylaryl triates and predictable reactivity of aryne intermediates by the aryne distortion model. 14 A plausible reaction mechanism is shown in Fig. 4A. First, the nucleophilic addition of the sulfur atom of alkynyl suldes onto arynes and following cyclization to the alkyne carbon construct the benzothiophene skeleton. Then, protonation of the resulting zwitterionic intermediate IV leads to benzothiophene 3a. To examine the proton source, we then performed control experiments using deuterated compounds (Fig. 4B-D). Treatment of o-silylaryl triate 1a and alkynyl sulde 2a dissolved in CD 3 CN with cesium uoride provided benzothiophene 3a with partial incorporation of deuterium through sulfonium intermediate V-d (Fig. 4B). 9b, 15 The reaction using deuterium-labeled ethyl p-tolylethynyl sulde 2a-d in acetonitrile also resulted in partial deuterium incorporation, suggesting intramolecular deuteration of zwitterionic intermediate IV-d with liberating ethylene (Fig. 4C). 9m An alternative proton source would be water in the reagents used, since deuterium was incorporated when the reaction was performed in the presence of deuterium oxide (Fig. 4D). Moreover, 2-chloro-6-(triuoromethanesulfonyl)phenyl ethyl ether (4) was detected as a side-product in the synthesis of 3a, clearly showing that 2chloro-6-(triuoromethanesulfonyl)phenolate intermediate VII was generated from 1a via the thia-Fries rearrangement of silicate intermediate VI, 16 and cesium phenolate VII was involved in the deethylation process of sulfonium intermediate V (Fig. 4E). Thus, possible protonation and deethylation mechanisms from zwitterionic intermediate IV were supported by these results.
We succeeded in the preparation of C3-functionalized benzothiophene 10 from alkyne 8 and aryne precursor 1a through C-C cleavage of carboxylic acid 9 by virtue of the good accessibility of alkynyl suldes and broad substrate scope of the aryne  This journal is © The Royal Society of Chemistry 2020 Chem. Sci., 2020, 11, 9691-9696 | 9693 reaction (Fig. 6A). Indeed, latently transformable alkynyl sulde 2l was synthesized from terminal alkyne 8 and S-ethyl p-toluenethiosulfonate catalyzed by CuI/xantphos under mild conditions. 12e Following aryne reaction between 2l and o-silylaryl triate 1a and subsequent removal of the tetrahydropyranyl (THP) group successfully afforded benzothiophene 3w having chloro and hydroxymethyl groups. Then, carboxylic acid 9 was prepared by oxidation with tert-butyl hydroperoxide catalyzed by copper(II) bromide. 18 Considering that recent remarkable achievements for transformations of the carboxy group into a range of functional groups such as halogens, phosphorus moieties, and aryl groups through C-C cleavage, 19 diverse C3functionalized benzothiophenes will be synthesized from benzothiophene 9. For example, decarboxylative iodination of 9 took place smoothly to provide 4-chloro-3-iodobenzo [b]thiophene (10) in high yield. 19b Thus, a wide variety of benzothiophenes can be synthesized through the aryne reaction between alkynyl sulde 2l and o-silylaryl triates and decarboxylative transformations.
We achieved the synthesis of benzothiophene 12 bearing four different aryl groups by virtue of the halogen-tolerated benzothiophene synthesis and the versatility of C2-position (Fig. 6B). Indeed, direct C-H arylation of benzothiophene 3t with 4-iodoanisole proceeded smoothly to provide 11 in moderate yield keeping bromo and chloro groups intact. 17i Then, a sequential Suzuki-Miyaura cross-coupling of 11 with 4-(triuoromethyl)phenyboronic acid and phenylboronic acid at the bromo and chloro group, respectively, successfully furnished 2,3,4,6-tetraarylbenzothiophene 12. This modular synthetic route would enable the preparation of diverse multiarylated benzothiophenes using various alkynyl suldes, aryl iodides, and arylboronic acids. 20 The good accessibility of o-silylaryl triates and alkynyl suldes realized the synthesis of polycyclic aromatic compound 14 (Fig. 6C). Firstly, the treatment of 6,7-thienobenzyne precursor 1k and alkynyl sulde 2e with cesium uoride afforded dithienobenzene 3x in moderate yield. Then, C2-iodination was realized by deprotonation with LDA followed by the addition of iodine. Finally, palladium-catalyzed amination at C2 of benzothiophene with p-toluidine and subsequent cyclization proceeded efficiently to afford pentahelicene analog 14. This result clearly demonstrated an advantage of the benzothiophene synthesis by the aryne reaction with alkynyl suldes enabling to prepare p-extended benzothiophenes having functional groups such as halogens. The benzothiophene synthesis will serve in the synthesis of various polyaromatic analogs containing benzothiophene skeleton. 21

Conclusions
In summary, we have developed a facile one-step synthetic method of benzothiophenes from o-silylaryl triates and alkynyl suldes. The wide scope of the benzothiophene synthesis and the versatile C2-functionalizations enabled the synthesis of a variety of multisubstituted benzothiophenes, which is difficult by the conventional methods. Further studies to clarify the reaction mechanism and to expand synthesizable multisubstituted benzothiophenes involving three-component couplings, and applications to synthesize analogs of bioactive compounds are currently underway.

Conflicts of interest
There are no conicts to declare. Notes and references