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Recent advances in the synthesis of benzo[b]thiophene fused polycyclic derivatives: Strategies and reactions

Jiali Huang ,  Wenyang Wang ,  Lei Zhang ,  Xiangtai Meng

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Citation:  Jiali Huang, Wenyang Wang, Lei Zhang, Xiangtai Meng. Recent advances in the synthesis of benzo[b]thiophene fused polycyclic derivatives: Strategies and reactions[J]. Chinese Chemical Letters, 2023, 34(6): 108003. doi: 10.1016/j.cclet.2022.108003 shu

Recent advances in the synthesis of benzo[b]thiophene fused polycyclic derivatives: Strategies and reactions

English

  • 1. Introduction

    Benzo[b]thiophene with a unique hybrid skeleton is an important core component for the construction of benzo[b]thiophene fused heterocycles, which have been widely used in the synthesis of organic compounds, multifunctional materials and drug molecules. Benzo[b]thiophene fused compounds not only have unique chemical properties and biological activities, but also have excellent pharmacological properties and metabolic stability. They are widely present in organic functional materials [1-8] and drug molecules, such as NU7441 [9] and Y-931 (Fig. 1) [10]. The synthesis of multifunctional benzo[b]thiophene fused heterocycles plays an important role in the fields of organic synthesis methodology and functional material chemistry and have attracted extensive attention of scientists in recent years [11-14].

    Figure 1

    Figure 1.  Pharmaceuticals and bioactive molecules containing benzo[b]thiophene scaffolds.
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    In recent years, chemical researchers have made great progresses in the efficient construction of benzo[b]thiophene fused heterocycles, and a series of versatile synthetic methods have been exploited on the basis of the reactivities of thioaurone, thioisatin, benzo[b]thiophene, and azadiene.

    Scheme 1 shows four classic pathways for the synthesis of benzo[b]thiophene fused cyclic compounds. In the first one, thioaurone reacts with a 1,3- or 1,4-dipolar zwitterion, which is followed by proton transfer, and the final addition/elimination process gives the product (Scheme 1A). In the second one, the C-S bond cleavage of thioisatin by nucleophilic attack of an amine leads to a sulfur anion intermediate, which undergoes a nucleophilic S-alkylation with α-haloketones, annulation, dehydration, and intramolecular nucleophilic addition, in succession, to give benzo[b]thiophene fused heterocycles (Scheme 1B). In the third one, the addition of a five-membered metallacycle to the C2 position of benzo[b]thiophene through C—H activation results in C2-metallation, which is followed by an elimination process to generate a biaryl compound. Afterwards, it may undergo a cyclization process to give the corresponding product, or continue a further reaction at the β-position of benzo[b]thiophene skeleton under the catalysis of metal catalyst to afford the desired product through a reductive elimination step (Scheme 1C). In the last one, Morita−Baylis−Hillman (MBH) carbonate expels a CO2 and tert–butoxy anion under the action of a Lewis base and then undergoes a γ-addition reaction with azadiene to generate a remote zwitterion intermediate with two resonance structures. Finally, an intramolecular substitution reaction with the removal of the catalyst 4-dimethylaminopyridine (DMAP) produces the final product (Scheme 1D).

    Scheme 1

    Scheme 1.  Classic pathways for the synthesis of benzo[b]thiophene fused cyclic compounds.
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    The following sections will summarize the advances on the construction of benzo[b]thiophene fused polycyclic derivatives in the last decade, including the contributions of our group and others, with a particular attention paid to the reaction mechanism (Scheme 1). The applications of these benzo[b]thiophenes are beyond the scope of this review.

    2. Synthesis of benzo[b]thiophene fused polycyclic derivatives from substituted benzo[b]thiophene

    2.1 The [3 + 2] annulation reaction of substituted benzo[b]thiophenes

    Benzo[b]thiophenes have various practical functions and are present in many pharmaceutical drugs and organic semiconductor materials [15-18]. In recent years, a number of methodologies have been developed on the basis of [3 + 2] annulation reaction of benzo[b]thiophenes for the synthesis of various benzo[b]thiophene fused polycyclic derivatives. In 2014, Ramasastry et al. designed a solvent-free domino reaction to form cyclopentannulated benzo[b]thiophenes (4 and 5) from benzothienyl carbinols (1 and 2) and 1,3-dicarbonyls 3 under the condition of polyphosphoric acid (PPA) (Scheme 2) [19]. Mechanistic investigation suggested that 1a initially reacted with 3a to produce intermediate A, and a subsequent intramolecular cyclization formed intermediate B, which could be converted to intermediate C through elimination of H2O. Then, species D, another resonance structure of C, evolved to intermediate E by loss of a proton. Finally, E could be converted to either 4a via path a or 4b via path b.

    Scheme 2

    Scheme 2.  Synthesis of cyclopentannulated benzo[b]thiophenes by solvent-free domino reaction.
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    In 2018, Yuan et al. developed a highly efficient dearomative reaction for the synthesis of benzo[b]thiophene fused polycyclic derivatives 8 from 3-nitrobenzo[b]thiophenes 6 and 3-isothiocyanato oxindoles 7 (Scheme 3a) [20]. The use of Zn(OTf)2 and chiral ligand L-1 as catalyst gave a series of benzo[b]thiophene fused polycyclic derivatives 8 in excellent yields with high enantioselectivities and diastereoselectivities. However, no product was observed for the reaction with 2-methyl-3-nitrobenzo[b]thiophene due to a steric hindrance. Gram scale experiments gave the desired product in 99% yield, demonstrating the practicality of this strategy.

    Scheme 3

    Scheme 3.  The dearomative reaction of benzo[b]thiophenes.
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    In the same year, Yuan et al. also reported the reaction between 2-nitrobenzo[b]thiophenes 9 and 3-isothiocyanato oxindoles 7 with the same catalyst as that in Scheme 3a in a different solvent (Scheme 3b) [21]. Broad substrate scope was verified by the observation that substrates with various substituents at the N position or various groups on the aromatic rings were well tolerated to afford the cycloadducts 10 in excellent yields with high dr and ee (up to >99:1 dr and >99% ee). They proposed a possible transition state (TS-2) to understand the stereochemistry during the formation of cycloadducts 10. Dearomative annulation of heteroarenes has become an effective way for the construction of polycyclic heterocycles [22]. In the subsequent work, Yuan and co-workers developed a Cat-1-catalyzed dearomative reaction of 2-nitrobenzo[b]thiophenes 9 and 3-isothiocyanato oxindoles 7 in methyl tert–butyl ether (MTBE) in 2021 (Scheme 3c) [23]. Followed by treating with K2CO3 and CH3I in acetone, the reaction successfully furnished a wide range of polycyclic heterocyclic products 11 with consistent (R, R, S) configurations. Experimental results demonstrated the efficiency of this reaction and the potential for building benzo[b]thiophene fused polycyclic derivatives.

    In 2019, Yuan's group reported a Ph2PMe-catalyzed [3 + 2] cyclization of 2-nitrobenzo[b]thiophenes 9 or 3-nitrobenzo[b]thiophenes 6 with allenoates 12 (Scheme 4) [24]. A wide range of structurally diverse cyclopenta[b]benzothiophenes (13 and 14) were obtained in good to excellent yields. A plausible reaction mechanism was shown in Scheme 4. Catalytic Ph2PMe was first added to the sp-carbon atom of 2,3-butadienoate 12 to form intermediate A, which gave intermediate B through a conjugate addition with 9. Intermediate C was formed by an intramolecular annulation process and then was converted into intermediate D through an intramolecular proton shift process. Finally, intermediate D released Ph2PMe and afforded product 13.

    Scheme 4

    Scheme 4.  Ph2PMe-catalyzed reaction of nitrobenzo[b]thiophenes and allenoates.
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    In 2020, Wang et al. investigated a new approach for the synthesis of fused tricyclic benzo[b]thiophene compounds (16 and 17) from nitrobenzo[b]thiophenes (6 and 9) and nonstabilized azomethine ylides 15′ (Scheme 5a) [25]. Optimizations of experimental variables showed that CH2Cl2 solution of trifluoroacetic acid (TFA) at room temperature was the best choice. This method efficiently gave the corresponding products in good to excellent yields. In 2021, Wang's group found the ability of Cat-2 to catalyze the reaction of 2-nitrobenzo[b]thiophenes 9 and azomethine ylides 18 (Scheme 5b) [26]. The transformation proceeded through an asymmetric Michael/Mannich cascade reaction and successfully furnished the desired dihydrobenzo[b]thiophene polycyclic products 19. They proposed plausible catalytic cycles of the reaction in Scheme 5b. The initial reaction of Cat-2 with 18 through a deprotonation process produced intermediate A, which subsequently underwent a Michael addition with 9, via transition state B, to form Michael adduct C. Intermediate E was generated through an intramolecular Mannich reaction, via transition state D, and eventually evolved to the desired product 19.

    Scheme 5

    Scheme 5.  The [3 + 2] reaction of nitrobenzo[b]thiophenes and azomethine ylides.
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    In 2019, Yuan's group performed the reaction of ethyl 4-mercapto-2-butanoate 20 with 6 using different catalysts and temperatures (Scheme 6) [27]. With the use of Cat-3 or Cat-4 as the catalyst for the case of X = S or X = N-R in 6, respectively, a series of chiral benzo[b]thiophene heterocyclic molecules 21 or tetrahydrothiopheneindoline derivatives 22 were obtained in good to excellent yields, providing a creative method to access these two types of compounds.

    Scheme 6

    Scheme 6.  Organocatalytic asymmetric dearomatization reaction of 3-nitroindoles and 3-nitrobenzo[b]thiophenes with ethyl 4-mercapto-2-butenoate respectively.
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    In 2021, John's group discovered a metal-free, one-pot reaction for the synthesis of benzo[b]thiophene-fused heteroacenes (24, 26 and 28) (Scheme 7) [28]. 3-Nitrobenzo[b]thiophenes 6 were employed to react with various phenols (23, 25 and 27) in the presence of KOH and EtOH at 80 ℃. The reaction mechanism suggested that phenol 27 first reacted with 6 to form intermediate A, which was followed by an intramolecular cyclization to give intermediate B. Finally, intermediate B was converted to 28 by eliminating HNO and H2O.

    Scheme 7

    Scheme 7.  The metal-free one-pot reaction of 3-nitrobenzo[b]thiophenes and various phenols.
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    2.2 The [4 + 2] annulation reaction of benzo[b]thiophenes

    The [4 + 2] cycloaddition reaction has been proved to be one of the most effective methods to obtain polycyclic heterocyclic skeletons and also a powerful way to construct multifunctional benzo[b]thiophene-fused heterocycles. In 2014, Mohanakrishnan et al. developed an efficient method for the preparation of benzo[b]thiophene-annulated heterocycles 31 in CH2Cl2 via a Lewis acid/Bronsted acid mediated cyclization of substituted benzo[b]thiophenes 29 and 2,5-dimethoxytetrahydrofuran 30 (Scheme 8) [29]. This reaction used 30 as the four-carbon synthon and successfully gave the target products 31 in good to excellent yields.

    Scheme 8

    Scheme 8.  Synthesis of benzo[b]thiophene-annulated heterocycles from substituted benzo[b]thiophenes and 2,5-dimethoxytetrahydrofuran.
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    In the same year, Chen's group developed an asymmetric dearomatic Diels-Alder reaction of maleimides 32 and benzo[b]thiophene derivatives (33, 35 and 37) under the catalysis of cinchona-based primary amine Cat-5. Benzo[b]thiophene-fused derivatives with different configurations (34, 36 and 38) were obtained in excellent yields under different conditions (Scheme 9) [30].

    Scheme 9

    Scheme 9.  Synthesis of fused benzo[b]thiophene derivatives via Diels-Alder reaction.
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    In 2019, Noland and co-workers developed a Diels-Alder reaction between maleimides 32 and 2-(1′-cycloalkenyl)benzo[b]thiophene 39 to produce dibenzo[b,d]thiophene derivatives (40 and 41) in excellent yield (Scheme 10) [31]. The cycloalkenyl group at C2 position of benzo[b]thiophene could be five-, six-, seven-, eight- and twelve-membered rings, broadening the substrate range of the reaction. The use of N-phenylmaleimides generated normal Diels-Alder adducts 40, while the use of N-methylmaleimide generated rearranged Diels-Alder adducts 41.

    Scheme 10

    Scheme 10.  Synthesis of dibenzo[b,d]thiophene derivatives via Diels-Alder reaction.
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    In 2019, Yuan et al. developed an aza-Michael/Michael addition cascade reaction between 2-nitrobenzo[b]thiophenes 9 and 2-aminochalcones 42 in the presence of CH2Cl2 at room temperature, with the use of chiral bifunctional squaramide Cat-4 as the catalyst (Scheme 11) [32]. The reaction enabled the synthesis of chiral benzo[b]thiophene fused heterocyclic compounds 43 under mild reaction conditions. It was worth noting that higher yields were obtained using 2-nitrobenzofuran derivatives (X = O) as substrates than using 2-nitrobenzo[b]thiophene derivatives (X = S). The authors proposed two transition state models (TS-4 and TS-5) involving intramolecular aza-Michael addition and intramolecular Michael addition, respectively.

    Scheme 11

    Scheme 11.  Synthesis of heterocyclic fused compounds by aza-Michael/Michael addition cascade reaction.
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    In 2016, the first enantioselective [4 + 2] cycloaddition of 3-nitrobenzo[b]thiophenes 6 with 2,4-dienals 44 was established by Jørgensen's group (Scheme 12) [33]. The use of Cat-6 as the catalyst and 1,4-diazobicyclo[2.2.2]octane (DABCO) as the additive delivered chiral benzo[b]thiophene fused cycloadducts 45 in moderate to good yields with moderate to excellent enantioselectivities. Mechanistic studies suggested that the reaction proceeded through asynchronous/stepwise addition and elimination processes, and the transition states (TS-6 and TS-7) of the addition and elimination steps were presented in Scheme 12.

    Scheme 12

    Scheme 12.  Synthesis of benzo[b]thiophene-fused derivatives from benzo[b]thiophene derivatives and 2, 4-dienals derivatives.
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    In 2018, Xu's group reported Cat-7 catalyzed cyclization of benzo[b]thiophene-3-carbaldehydes 46 and nitroolefins 47 to afford tetrahydrodibenzo[b]thiophene derivatives 48 in good to excellent yields with high enantioselectivities (Scheme 13) [34]. From the viewpoint of reaction mechanism, 46 first reacted with nitroolefins 47 to form intermediate A under the catalysis of Cat-7, which was followed by an asymmetric Michael addition process to form intermediate B. Subsequently, intermediate B was converted to C through an intramolecular nitro-aldol reaction with release of Cat-7. Finally, the desired product 48 was produced by a dehydration/reduction process from 47.

    Scheme 13

    Scheme 13.  Synthesis of tetrahydrodibenzo[b]thiophene derivatives from benzo[b]thiophene-3-carbaldehydes and nitroolefins.
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    As powerful tools in organic synthesis, N-heterocyclic carbene (NHC) organocatalysts have attracted extensive attention in recent years [35-38]. In 2020, Li's group reported an oxidative cascade reaction between 2-nitrobenzo[b]thiophene 9 and β-substituted crotonaldehydes 49 in the presence of the NHC catalyst Cat-8 and 4,4′-diphenoquinone (DQ). This strategy rapidly accessed a series of 4-hydroxydibenzo[b]thiophenes 50 in moderate to good yields (Scheme 14a) [39]. In 2021, Ye's team put forward a methodology for the enantioselective synthesis of a series of chiral benzo[b]thiophene-fused biaryls 53, by using 2-benzylbenzo[b]thiophene-3-carbaldehydes 51 and β-aryl enals 52 as substrates, Cat-9 as the NHC catalyst, DQ as oxidant, 1,8-diazabicylo-[5.4.0]undec–7-ene (DBU) as base, and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) as the second oxidant (Scheme 14b) [40]. This methodology benefited from a broad substrate scope and unique chemoselectivity. Gram-scale experiments furnished the desired products in high yields (up to 92% yield) and high enantioselectivities (up to 98% ee), which disclosed the practicality of the strategy and provided an efficient route for the synthesis of axially chiral benzo[b]thiophene-fused biaryls.

    Scheme 14

    Scheme 14.  Synthesis of benzo[b]thiophene-fused derivatives via NHC catalysis.
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    In recent years, transition-metal-catalyzed cyclization reaction has emerged as a highly efficient strategy for building benzo[b]thiophene fused heteroaromatic compounds [41-44]. In 2017, Itami's group developed an efficient π-extension reaction of benzo[b]thiophenes 29 with 9,9-dimethyldibenzosiloles 54 to produce benzo[b]thiophene-fused heteroarenes 55 (Scheme 15) [45]. Under the palladium/o-chloranil catalytic system, the π-extended fused heteroarenes 55 could be obtained in a single step. A possible reaction pathway was proposed by the authors. The reaction was initiated by the formation of intermediate A, which reacted with benzo[b]thiophene 29a to form β-biphenyl-α-palladated adduct B. Subsequently, B underwent a β-H elimination/demetallation processes to give intermediate C, which was further converted to intermediate D through the sequential transmetalation and carbopalladation processes. Finally, product 55a was obtained by a β-H elimination/demetallation process from intermediate D.

    Scheme 15

    Scheme 15.  Pd-catalyzed cyclization of benzo[b]thiophenes with 9,9-dimethyldibenzosiloles.
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    In 2019, Xia and co-workers reported the palladium-catalyzed reaction of O-methylketoxime 56 with styrenes 57. Under the catalysis of Pd(OAc)2 in AcOH at 110 ℃, a series of benzothienopyridines 58 were obtained in moderate yields (Scheme 16) [46]. The reaction mechanism showed that intermediate A was formed by coordination of 56 to Pd(OAc)2 and then was converted to intermediate B. Ring-open of intermediate B led to intermediate C, which was further transformed into intermediate D with release of AcOH and Pd(0). The oxidative insertion of Pd(0) into the N-O bond resulted in intermediate E, which evolved to intermediate F by the C-N bond formation and N-O bond cleavage. Finally, product 58 was obtained after a β-hydride elimination process from intermediate F.

    Scheme 16

    Scheme 16.  Pd-catalyzed synthesis of benzothienopyridines.
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    In 2019, You's group reported a rhodium-catalyzed annulation between benzo[b]thiophenes 29 and 1-(methylthio)naphthalene derivatives 59 in the presence of Ag2O and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) for the construction of polycyclic benzo[b]thiophene-fused derivatives 60 (Scheme 17) [47]. In the proposed reaction mechanism, 1-(methylthio)naphthalene 59a initially coordinated to Cp*RhⅢX2 to form intermediate A, which reacted with benzo[b]thiophene 29a to give intermediate B. The following reductive elimination process generated intermediate C. The released Cp*RhⅠ was converted to Cp*RhⅢX2 to re-engage in the catalytic cycles by the oxidation of AgⅠ. Then, intermediate C underwent a single electron transfer (SET) process to give intermediate D, after which intermediate E was formed via an electrophilic cyclization/demethylation process. Finally, E was converted to intermediate F by the oxidation of Ag2O, and the expected product 60a was produced after deprotonation.

    Scheme 17

    Scheme 17.  Rh-catalyzed annulation reaction of benzo[b]thiophenes with naphthalene derivatives.
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    In 2021, the same research group disclosed a rhodium-catalyzed cascade annulation of phenacyl phosphoniums 61 and benzo[b]thiophenes 29 (Scheme 18) [48]. The use of [RhCp*Cl2]2 as catalyst efficiently prepared a series of benzo[b]thiophene fused polycyclic compounds 62. The authors proposed two catalytic cycles (Cycle Ⅰ and Cycle Ⅱ) as the candidates of the real reaction pathway. First, 61a was transformed into 61aa in the presence of CsOAc, which reacted with [RhⅢCp*] to yield intermediate A. Intermediate A reacted with 29a to form intermediate B, and a following β-H elimination process gave intermediate C. Then, a C-O bond coupling at C afforded intermediate D, which underwent β-H elimination to provide intermediate E and [RhⅠCp*]. The released [RhⅠCp*] was converted to [RhⅢCp*] by the oxidation of Ag2O to complete the catalytic cycle (Cycle Ⅰ). Intermediate E was further converted to intermediate F by C-H activation, followed by a reaction with 29a to yield intermediate G. Then, intermediate G underwent β-H elimination to form intermediate H, and a C-C bond coupling at H gave intermediate I. Finally, the β-H elimination of I led to the formation of the target product 62a and regeneration of [RhⅠCp*] (Cycle Ⅱ).

    Scheme 18

    Scheme 18.  Rh-catalyzed cascade annulation of phenacyl phosphoniums and benzo[b]thiophenes.
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    Iridium-catalyzed annulation reactions of benzo[b]thiophene derivatives 29 have been developed for the construction of benzo[b]thiophene-fused polyheterocycles. In 2018, Yang and co-workers reported [IrCp*Cl2]2-catalyzed oxidative cyclization of α-keto carboxylic acids 63 and benzo[b]thiophenes 29 (Scheme 19) [49]. A series of benzothieno[3,2-c][2]benzopyranones derivatives 64 were successfully obtained with the highest yield of up to 90%. The mechanism was investigated by deuterium-labeling experiments. First, [IrCp*X2]2 reacted with AgNTf2 to form [IrⅢ], followed by the coordination of α-keto acid 63a to produce intermediate A. Subsequently, a C-H activation occurring at the C2 position of benzo[b]thiophenes 29a delivered intermediate B, and the following reductive elimination process gave intermediate C and [IrⅠ]. Intermediate C was converted to intermediate D by decarboxylation in the presence of Ag2O, which was further converted to intermediate E by Ag-mediated oxidation. Then, a nucleophilic attack of H2O transformed intermediate E into intermediate F, followed by C-H iridation to give intermediate G. Reductive elimination of intermediate G resulted in the formation of the final product 64a with release of [IrⅠ], which was reoxidized to [IrⅢ] by Ag2O to finish the catalytic cycle (path a). Alternatively, 63a could first be converted to benzoic acid H through a decarboxylation process, followed by a carbonyl directed C-H activation to afford intermediate I (path b). Subsequent reaction of intermediate I with 29a generated intermediate J. Reductive elimination from J resulted in intermediate F and [IrⅠ], and the processes from [IrⅠ] to the final product 64a were the same as those of path a. The authors pointed out that path a may be the main route due to the low efficiency of carboxylic acid H, but path b could not be ruled out at this stage.

    Scheme 19

    Scheme 19.  Iridium-catalyzed oxidative cyclization of phenylglyoxylic acids with benzo[b]thiophenes.
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    In 2018, You et al. described a one-pot cyclization of benzo[b]thiophene derivatives 29 with (hetero)aromatic carboxylic acids 65 or α,β-unsaturated carboxylic acids 67. Under the catalysis of [IrCp*Cl2]2, various benzo[b]thiophene-fused derivatives (66 and 68) were obtained in moderate to good yields (Scheme 20a) [50]. This reaction provided a powerful strategy for the construction of polycyclic benzo[b]thiophene-fused compounds. In 2021, Yu et al. developed a tandem iridium-catalyzed cross-dehydrogenative coupling reaction of benzo[b]thiophene derivatives 29 and ketene dithioacetals 69, which delivered the target compounds 70 in moderate to good yields (Scheme 20b) [51]. They assumed that the reaction started from a ligand exchange between [Cp*IrCl2]2, AgSbF6 and Cu(OPiv)2, leading to the formation of [Cp*IrⅢ(OPiv)2]. The ketene dithioacetal 69a was then cyclometalated to give intermediate A. The reaction of intermediate A and benzo[b]thiophene 29a afforded intermediate B, and the next reductive elimination process gave species C and Cp*IrⅡ. Upon the promotion of Ag2O, C evolved to product 70a through a radical cyclization reaction. The Cp*IrⅡ was further converted to [Cp*IrⅢ (OPiv)2] under the oxidation of Ag2O and HOPiv.

    Scheme 20

    Scheme 20.  Synthesis of benzo[b]thiophene-fused derivatives via Iridium catalysis.
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    In 2018, Yang's group discovered that the reaction of 3-nitobenzo[b]thiophenes 6 and alkylidene malononitriles 71 could produce dibenzothiophen-1-amine derivatives 72 in the presence of triethyamine (TEA) under N2 atmosphere in CH3CN at 50 ℃, while the yields were not high (Scheme 21a) [52]. In 2020, Yuan and co-workers reported a base-mediated cyclization reaction of nitrobenzo[b]thiophenes derivatives (6 and 9) with α,α-dicyanoalkenes 73 (Scheme 21b) [53]. Under mild reaction conditions, a series of dibenzoheterocyclic compounds (74 and 75) were obtained in good to high yields. This [4 + 2] annulation exhibited a broad substrate scope, and the synthetic utility was well demonstrated by gram-scale experiments.

    Scheme 21

    Scheme 21.  Synthesis of benzo[b]thiophene derivatives via [4 + 2] annulation.
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    In 2020, Guo and co-workers reported a chiral phosphine-catalyzed enantioselective [4 + 2] cyclization between 3-nitrobenzo[b]thiophenes 6 and allenoates 76, affording chiral dihydrodibenzo[b]thiophenes 77 in good yields with high enantioselectivities. They proposed a mechanism for the reaction. First, allenoates 76 were converted to intermediate A under the catalysis of [PR3'], which further reacted with 6 to produce intermediate B. Subsequently, intermediate B underwent migration and intramolecular conjugate addition events to regenerate [PR3'] and form intermediate D. The desired product 77 was yielded by eliminating HNO2 from D (Scheme 22) [54].

    Scheme 22

    Scheme 22.  Phosphine-catalyzed [4 + 2] annulation of 3-nitrobenzo[b]thiophene with allenoates.
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    2.3 Other reactions

    Other approaches to access benzo[b]thiophene-fused compounds include [4 + 3] cycloaddition and [3 + 3] cycloaddition. In 2013, Li's group developed a [4 + 3] cycloaddition of benzo[b]thiophene-3-yl alcohols 78 with 1,3-cyclopentadiene 79 to afford benzo[b]thiophene-fused bicyclo[3.2.1]octa-2,6-dienes 80 in moderate to good yields at room temperature (Scheme 23) [55].

    Scheme 23

    Scheme 23.  Synthesis of benzo[b]thiophene-fused bicyclo[3.2.1]octa-2,6-dienes.
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    In 2018, Deng et al. developed an efficient approach for the synthesis of benzo[b]thiophene derivatives 83 via a [3 + 3] cycloaddition of N-Tosyl-3-aminobenzo[b]thiophenes 81 and α,β-unsaturated aldehydes 82 under the catalysis of Cat-11 (Scheme 24) [56]. Coupling reaction has been a powerful and straightforward strategy for the synthesis of various organic compounds [57-60]. In recent years, a large number of heterocyclic benzo[b]thiophene fused compounds have been efficiently constructed by means of a coupling reaction. In 2011, Knochel and co-workers reported a synthetic route for the preparation of benzo[4,5]thieno[2,3-b]indol derivatives 86 (Scheme 25) [61]. In the first step, 3-bromobenzo[b]thiophene 84 was used as substrate to obtain benzo[b]thiophen-3-yl zinc(Ⅱ) chloride, which underwent a Negishi cross-coupling reaction  with bromoaniline derivatives 85 in the second step. Lastly, the resulting products underwent oxidative cycloamination to afford the target products 86 in the presence of CuCl·2LiCl.

    Scheme 24

    Scheme 24.  Synthesis of benzo[b]thiophene-fused derivatives via [3 + 3] cycloaddition.
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    Scheme 25

    Scheme 25.  The synthetic route for the preparation of benzo[4,5]thieno[2,3-b]indole derivatives.
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    In 2021, Doye's group developed the reaction of amines 87 with 3-bromobenzo[b]thiophene derivatives 88 to generate benzo[b]thiophene-fused 6- or 7-membered ring compounds (89, 90 and 91) under three different titanium catalysts (Cat-12 or Cat-13 or Cat-14). The yields of the desired products were as high as 93% (Scheme 26) [62].

    Scheme 26

    Scheme 26.  The synthesis of benzo[b]thiophene-fused 6- or 7-membered ring compounds.
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    In 2015, Miura and co-workers reported a Pd(TFA)2-catalyzed intramolecular coupling reaction of 3-aryloxybenzo[b]thiophenes 92, which effectively constructed benzothieno[3,2-b]benzo-furans 93 in moderate to good yields (Scheme 27a) [63]. However, when a 2-naphthoxy group was installed on the C3 position of benzo[b]thiophene, the reaction produced two compounds and the yield dropped significantly. In 2015, Kuninobu and co-workers disclosed a palladium-catalyzed intramolecular oxidative C—H/C—H cross-coupling reaction of benzo[b]thiophene derivatives (94 and 96) (Scheme 27b) [64]. Benzo[b]thiophene fused heterocycles (95 and 97) with different structural types were obtained by using [Pd(OPiv)2] and AgOPiv as the catalyst and oxidant, respectively. The mechanism suggested that [Pd(OPiv)2] first reacted with 94 to give PivOH and intermediate A. Subsequently, a C—H bond activation transformed intermediate A into palladacyclic intermediate B with release of PivOH. Finally, intermediate B underwent a reductive elimination process in the presence of AgOPiv to afford the desired products 95 and regenerated [Pd(OPiv)2].

    Scheme 27

    Scheme 27.  Synthesis of benzo[b]thiophene derivatives by palladium-catalyzed coupling reaction.
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    In 2017, Suga's research group developed a dehydrogenative annulation reaction for the synthesis of benzosilolothiophene derivatives 100 (Scheme 28) [65]. Under the catalysis of [Rh(cod)Cl]2 and dppe-F20, 2-[2-(diphenylsilyl)phenyl]benzo[b]-thiophene and the analogues (98 and 99) could be transformed into benzosilolothiophenes 100  in moderate to excellent yields.

    Scheme 28

    Scheme 28.  Rh-catalyzed synthesis of benzo[b]thiophene-fused derivatives.
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    In 2018, You's group developed a novel C−H/C−H cross-coupling reaction of N-methylimidazolium salts 101 with benzofuran 102 or benzo[b]thiophene 29. Under the catalysis of RhCl3·3H2O, benzo[b]thiophene fused molecules (103 and 104) were successfully obtained (Scheme 29a) [66]. Experimental results indicated that both RhCl3·3H2O and trifluoroacetic acid anhydride (TFAH) played a crucial role in this reaction. In 2019, Lan et al. reported the construction of benzo[b]thiophene-fused derivatives from by Rh(Ⅲ)-catalyzed reaction of benzaldehydes 105 and benzo[b]thiophenes 29 (Scheme 29b) [67]. Two kinds of benzo[b]thiophene-fused polycyclic compounds (106 and 108) were obtained using β-alanine or 107 in HFIP at 120 ℃. On the other hand, when using BnNH2 in t-amyl alcohol (t-AmylOH) and/or 1,2-dichloroethane (DCE), ortho-benzo[b]thiophene benzaldehydes 109 were obtained and could be further transformed into benzo[b]thiophene-fused indanone derivatives 110 via an intramolecular dehydrogenative arylation process. The mechanism suggested that benzaldehyde 105 first reacted with RNH2 to generate intermediate A, which coordinated to Cp*RhⅢL2 and was subsequently converted to intermediate B by ortho-C-H activation. Intermediate B reacted with benzo[b]thiophene to give intermediate C, followed by the formation of intermediate D and release of Cp*RhⅠ that could be converted to Cp*RhⅢL2 to fulfill the catalytic cycle. Intermediate D was finally converted to 109 when BnNH2 was used in t-AmylOH and/or DCE, while 106 was obtained from intermediate D when β-alanine in HFIP was used.

    Scheme 29

    Scheme 29.  Rh-catalyzed reaction leading to polycyclic benzo[b]thiophene-fused derivatives.
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    In 2017, Zhu's group carried out an intramolecular C−O Ullmann reaction of 2-(3-bromobenzo[b]thiophen-2-yl)phenol derivatives 111 to construct benzoheterocyclic-fused core frameworks (Scheme 30) [68]. Under the catalysis of CuI and 1,10-phenanthroline, benzothieno[3,2-b]furan-fused heterocycles 112 were obtained in good to excellent yields (up to 97% yield).

    Scheme 30

    Scheme 30.  Synthesis of benzothieno[3,2-b]furan-fused heterocycles via intramolecular C−O Ullmann reaction.
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    In 2020, Suga's group reported a dehydrogenative cyclization of 2-(benzo[b]furan-2-yl)benzenethiol derivatives 113 in the presence of nBu4NBr (Scheme 31a) [69], providing an efficient approach for the synthesis of benzo[b]thiophene-fused thienoacenes 114. In 2021, the same group further developed this type of reaction to synthesize the compounds of similar structure. Under the catalysis of Cu(OAc)2, a variety of benzo[b]thiophene-fused furanobenzenes (116 and 118) were obtained (Scheme 31b) [70]. The intramolecular coupling reaction of 2-(benzo[b]thiophen-2-yl)phenols 115 or 2-(benzo-[b]thiophen-3-yl)phenols 117 in the mixed solvent of N-methyl-2-pyrrolidone (NMP), ethylene glycol monomethyl ether (EGM), and toluene at 145 ℃ under air could serve as an important synthetic route for the construction of benzo[b]thiophene fused heterocycles. The authors assumed that Cu species initially reacted with 115 to give intermediate A and carboxylic acid. Via transition state B, the formed intermediate A evolved to intermediate C and carboxylic acid. Finally, a reductive elimination at C led to the formation of 116 and release of CuLn, which could be recovered to the initial Cu species by carboxylic acid and O2 to restart the catalytic cycles. Notably, the process from the beginning to C was reversible.

    Scheme 31

    Scheme 31.  Dehydrogenative cyclization of benzo[b]thiophene derivatives.
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    Metal-free methodologies have also been widely utilized to access benzoheterocycle-fused compounds in the past few years. In 2016, Ramasastry et al. innovatively proposed an organophosphine-catalyzed intramolecular hydroalkylation of benzo[b]thiophen-3-ynones 119. Under the catalysis of PCy3, a range of pentannulated benzo[b]thiophene derivatives 120 were obtained in high yields and high stereoselectivities from benzo[b]thiophen-3-ynones 119 bearing different substituents (Scheme 32) [71]. The authors proposed two reaction pathways (part a and part b) to explain deuterium incorporation at the β-position and γ'-position. The results indicated that only deuterium incorporation at the γ'-position occurred during the reaction. The mechanism suggested that 119 first reacted with PCy3 to form intermediate A. Deuterium incorporation at the β-position of A gave intermediate B, and then, deuterium ion attacked intermediate B resulting in the formation of intermediate C. The removal of PR3 from C formed intermediate D, which was converted to intermediate E through enolization. The H/D exchange at the hydroxyl group by the presence of D2O led to intermediate F. Finally, the desired product (120a or 120a') was obtained after deuteration of intermediate F.

    Scheme 32

    Scheme 32.  PCy3-catalyzed intramolecular hydroalkylation of benzo[b]thiophen-3-ynones.
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    In 2019, Kitamura and co-workers developed a new strategy to synthesize [1]benzothieno[3,2-b][1]benzo[b]thiophene derivatives 114 from 1,2-bis(2-methylthiophenyl)-ethynes 121. In this method, 1,2-bis(2-methylthiophenyl)-ethynes 121 were first converted to 3-iodo-(2-methylthiophenyl)benzo[b]thiophenes 122 in the presence of I2 and PhI(OAc)2 at room temperature, which then underwent a photolysis reaction to generate [1]benzothieno[3,2-b][1]benzo[b]thiophene derivatives 114. At the same time, bis[1]benzothieno[2,3-d;2′,3′-d′]benzo[1,2-b;4,5-b′]dithiophene 123 was also obtained in high yield (94%) (Scheme 33a) [72]. In 2022, Procter et al. also reported a synthetic method to access [1]benzothieno[3,2-b][1]benzo[b]thiophene derivatives 114 (Scheme 33b) [73] through three processes. Under the catalysis of trifluoroacetic anhydride (TFAA), benzo[b]thiophene S-oxides 124 and phenols 27 first underwent a Pummerer CH–CH-type cross coupling reaction to form 2-(3-methoxybenzo[b]thiophen-2-yl)phenols 125, which were further transformed through a Newmann-Kwart reaction. The final cyclization process afforded the desired products 114. These reactions provided a useful route for the synthesis of bisbenzo[b]thiophene skeleton compounds.

    Scheme 33

    Scheme 33.  Synthesis of [1]benzothieno[3,2-b][1]benzo[b]thiophene derivatives.
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    In 2017, John and co-workers described an efficient method for the preparation of benzothieno[3,2-b]indoles 128 via a metal-free, one-pot three-component reaction of 3-nitrobenzo[b]thiophene 6, cyclohexanones 126 and primary amines 127 (Scheme 34) [74]. By means of this approach, various benzothieno[3,2-b]indoles 128 were obtained in satisfactory yields.

    Scheme 34

    Scheme 34.  The three-component reaction of 3-nitrobenzo[b]thiophene, cyclohexanones, and primary amines.
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    To overcome the difficulty in the synthesis of tetralones, Parsons's group developed an efficient approach to access 4-tetralones (130 and 132) by a transition-metal-free ring expansion of 1-(benzo[b]thiophen-2-yl)cyclobutan-1-ol derivatives (129 and 131) in 2018 (Scheme 35a) [75]. The reaction was carried out under mild conditions with commercially available reagents N-bromosuccinimide (NBS) and CH3CN. In 2020, the same research group further discovered that 4-tetralones 130 could be synthesized from 1-(benzo[b]thiophen-3-yl)cyclobutan-1-ols 133 by AgNO3-mediated ring expansion reaction. Moreover, the 1-(benzo[b]thiophen-3-yl)cyclobutan-1-ols 133 could also be converted to 1-tetralones 134 upon NBS-mediation, which provided a feasible method for the synthesis of different tetralone derivatives (Scheme 35b) [76]. In 2022, Zhu's group found that benzo[b]thiophene-substituted cyclobutanols 135 could be converted to 1-tetralones 130 in the presence of [Mes-Acr-Me]+BF4− and 1,4-dioxane (Scheme 35c) [77]. This reaction provided a facile way to access tetralones to afford the desired products 130 in moderate to good yields at air atmosphere.

    Scheme 35

    Scheme 35.  Synthesis of tetralone derivatives via ring expansion reactions.
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    3. Synthesis of benzo[b]thiophene fused cyclic compounds from benzo[b]thiophene-2,3-diones and their analogues

    Thioisatin has broad application prospects in the synthesis of sulfur-containing heterocyclic compounds. In recent years, our research group have made great progress in the construction of benzo[b]thiophene fused heterocyclic compounds from thioisatin. In 2020, we developed an efficient approach for the synthesis of benzo[b]thiophene fused pyrrolidone derivatives 139. This method proceeded through an eco-friendly, nontoxic three-component domino reaction of thioisatins 136, ethyl 4–chloro-3-oxobutanoate 137 and amines 138 in water, successfully obtaining a wide variety of benzo[b]thiophene fused pyrrolidone derivatives 139 (Scheme 36) [78]. The mechanism suggested that amine 138a initially attacked on the C2 position of 136a to form intermediate A. Then, A reacted with 137a to produce intermediate B, followed by an intramolecular nucleophilic addition to give intermediate C. Afterwards, intermediate D was generated by a N-nucleophilic addition. Finally, D underwent dehydration to form benzo[b]thiophene fused pyrrolidone derivative 139a.

    Scheme 36

    Scheme 36.  Synthesis of benzo[b]thiophene-fused pyrrolidone derivatives by three-component domino reaction.
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    In 2020, we proposed a synthetic method for the preparation of benzothiopheno[2,3-e]azepinedione derivatives 141 from thioisatins 136, ortho-Br α-bromoketones 140 and amines 138 by a three-component reaction (Scheme 37) [79]. This reaction was found to have a wide substrate range and high overall product yields (>63%). However, when α-bromoketones 143 were used instead of ortho-Br α-bromoketones 140, the desired benzo[b]thiophene fused seven-membered ring compounds 141 were not obtained and another benzo[b]thiophene derivatives 142 were obtained. The plausible mechanism was very similar to that of the reaction of thioisatins 136 with ethyl 4–chloro-3-oxobutanoate 137 and amines 138 (Scheme 36). The difference was that intermediate C underwent a dehydration reaction to give compound 142, and the latter species needed to be catalyzed by CuI under the premise that the substrate could only be ortho-Br α-bromoketones 140 to generate benzo[b]thiophene fused heterocycles 141.

    Scheme 37

    Scheme 37.  Synthesis of benzothiopheno[2,3-e]azepinedione derivatives by three-component reaction.
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    In the same year, our group reported that α-bromoketones 143 could be combined with thioisatins 136 and amines (138 and 145) to synthesize benzo[b]thiophene fused N-heterocycles 144 and benzo[b]thiophene-fused N-polyheterocyclic compounds 146 through a three-component domino reaction in DMF instead of H2O (Scheme 38) [80]. The highest yield of the target product could reach up to 94%. On the proposed reaction pathway, thioisatin 136a initially reacted with amine 145a to form intermediate A, which was followed by reaction with 2–bromo-1-phenylethan-1-one 143a to give intermediate B. An intramolecular cyclization of B constructed a five-membered ring to deliver intermediate C. Then, intermediate C was converted to intermediate D by dehydration, which reacted with another amine to generate intermediate E. An intramolecular nucleophilic addition transformed intermediate E into F. Finally, the desired benzo[b]thiophene-fused N-polyheterocyclic compound 146a was produced after deprotonation of F.

    Scheme 38

    Scheme 38.  Synthesis of benzo[b]thiophene fused N-heterocycles by three-component domino reaction.
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    In the subsequent work, we further extended the three-component domino reaction of thioisatins 136 with α-bromoketones 143 and amines. It was found that benzo[b]thiophene-fused polycyclic compounds 148 and benzo[b]thiophene-fused eight-membered N-heterocycles 149 were obtained by using two types of tryptamines 147 to react with thioisatins 136 and α-bromoketones 143 in DMF at 150 ℃ (Scheme 39) [81]. The generality and practicability of this reaction have been verified by gram scale experiments and transformation experiments. The mechanism showed that thioisatin 136 initially reacted with tryptamine 147a to form intermediate A, which was followed by reaction with α-bromoketones 143a to give intermediate B. An intramolecular cyclization delivered intermediate C, and the following dehydration process generated intermediate D. When R3 = H, intermediate D was converted to intermediate E. Finally, benzo[b]thiophene-fused polycyclic compound 148a was formed from E. However, When R3 = CO2Me, the conversion of intermediate C to F took place, possibly due to the influence of steric hindrance. Subsequently, intermediate F was transformed into intermediate G, followed by decarbonylation to generate intermediate H. Finally, benzo[b]thiophene-fused eight-membered N-heterocycle 149a was produced by dehydration of H.

    Scheme 39

    Scheme 39.  Synthetic route to benzo[b]thiophene-fused polycyclic compounds and benzo[b]thiophene-fused eight-membered N-heterocycles.
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    In 2021, we reported a stereo-tunable domino reaction of thioisatins 136 with α-bromoketones 143 and cyclohexane1,2-diamines (150 and 152) (Scheme 40) [82]. The desired products 151 or 153 could be selectively obtained by using cyclohexane1,2-diamines with different stereo configurations (150 and 152). In the reaction mechanism, the processes from thioisatin to intermediate D were similar to the reaction mechanism of thioisatins 136 and α-bromoketones 143 with amines (138 and 145) (Scheme 38), but the processes after intermediate D were different. With the use of 152, benzo[b]thiophene fused eight-membered N-heterocycle 153a was formed. In contrast, the use of 150 facilitated the transformation of intermediate D into E, which was converted to benzo[b]thiophene-fused polycycle 151a. As another approach to access benzoheterocycle-fused compounds, the domino reaction between thioisatins 136 and α-bromoketones 143 was reported by our research group in 2021 (Scheme 41) [83]. This approach was simple and versatile, and what's more, and the high selectivity for the formation of two types of sulfur-containing heterocyclic compounds (154 and 155) was easily controlled by the presence or absence of MgSO4. By using MgSO4 and K2CO3 at CH3CN in reflux situation, the reaction successfully afforded a series of benzo[b]thiophene fused pyranones 154 in good to excellent yields (up to 95% yield).

    Scheme 40

    Scheme 40.  Approach to the synthesis of benzo[b]thiophene-fused heterocyclic derivatives.
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    Scheme 41

    Scheme 41.  The domino reaction between thioisatins and α-bromoketones.
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    4. Synthesis of benzo[b]thiophene fused cyclic compounds from (Z)-benzylidenebenzo[b]thiophen-3(2H)-ones and their analogues

    As central building blocks of benzo[b]thiophene condensates, thioaurones can undergo cyclization reaction with a variety of organic compounds, and the produced benzo[b]thiophene derivatives have many important applications in different fields. In 2016, Albrecht's research group reported a [4 + 2] cyclization between 2-alkylenebenzo[b]thiophene-3(2H)-ones 156 and dienamines 157 (Scheme 42) [84]. Thioaurones were used as heterodienes for the synthesis of benzo[b]thiophene skeletons, and the enantioselectivity was based on the principle of steric shielding by utilizing the particular amino catalyst Cat-15. The mechanism showed that Cat-15 was first condensed with unsaturated aldehyde 157a, together with deprotonation and isomerization, to provide dienamine A. Then, the [4 + 2] reaction between B and 156a occurred via transition state B to generate enamine C, and the s-cis conformation of 156a was fixed. The final hydrolysis yielded the desired product 158a.

    Scheme 42

    Scheme 42.  The cycloaddition of thiouranone to dienamines.
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    In 2017, our group investigated the reaction between thioaurones 156 and sulfur ylide 160. Using NaH as the catalyst, [4 + 3] cyclization occurred to delivered the products 161 in high yields (Scheme 43a) [85]. In 2018, we conducted an in-depth study by using different catalysts in the domino reaction of thioaurones 156 with sulfur ylide 162 (Scheme 43b) [86]. In this work, sulfur ylide was used as a two-carbon synthon to engage in a [4 + 2] cyclization with thioaurone. The products 163 containing a pyran ring were generated under the catalysis of Cs2CO3, while the products 164 were generated under the catalysis of N,N-Diisopropylethylamine (DIPEA).

    Scheme 43

    Scheme 43.  Cyclization of thioherones with allyl thiylides on different carbon atoms.
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    In the same year, we also studied the domino reaction between thioaurones 156 and phosphorus ylides 165, with the latter species being similar to allyl sulfur ylides (Scheme 44a) [87]. As compared to sulfur ylides, the phosphorus ylides with different conjugation lengths were investigated. Although the same [3 + 3] cyclization occurred, the resulting products 166 and 167 were different. In 2019, we employed cinchonidine or NaOH to promote the reaction of thioaurones with phosphorus ylides to form benzo[b]thiophene fused tricyclic backbone (Scheme 44b) [88]. When thioaurones (168 and 169) containing ɑ,β-unsaturated aldehydes were used to react with phosphorus ylides 170 by different base catalysts, the umbrella-shaped oxatricycles 171 and 172 with high stereoselectivity were obtained in good yields.

    Scheme 44

    Scheme 44.  Research on thiourea ketones and allyl phosphorus ylides.
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    In 2017, we explored the reaction of thioaurones 156 with MBH carbonate 173 (Scheme 45a) [89]. In this work, different solvents were screened to control the domino reaction. The benzo[b]thiophene-fused pyran derivatives 174, the oxacyclic cycloheptadienes 175 and the oxatricyclodecene compounds 176 were obtained by using THF, EtOH, and N,N-diethylformamide (DEF)/H2O as solvent, respectively. In 2020, we expanded our research to thioaurones 177 and MBH carbonate 173 (Scheme 45b) [90] and disclosed a novel phosphorus-catalyzed domino reaction. The benzo[b]thiophene fused [6–5–5–6–6] pentacyclic skeleton was constructed using PPh3 as catalyst, and 178 and 179 were obtained with different stereoselectivities.

    Scheme 45

    Scheme 45.  Research on the correlation between thiourea ketones and MBH carbonates.
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    In 2018, we performed a [4 + 2] annulation of thioaurones 156 and benzyl allenoates 180 (Scheme 46a) [91]. The benzothieno[3,2-b]pyran derivatives 181 were obtained by refluxing in toluene under the efficient catalysis of tris(4-methoxyphenyl)phosphorus. In the same year, we investigated the domino reaction of thioaurones 182 with allenoate 183 (Scheme 46b) [92]. A series of bridged bicyclic benzo[b]thiophene-fused dioxabicyclo[3.3.1]nonane derivatives 184 were obtained in the presence of tris(4-methoxyphenyl)phosphorus catalyst. In 2019, we further studied the tandem reaction of thiouranones 156 with allenoate 183 (Scheme 46c) [93]. Using DABCO as the catalyst of the [4 + 2] cyclization, two different benzo[b]thiophene derivatives 185 and 186 were obtained in good yields. In the same year, Veselý's group developed a cycloaddition reaction of 3-alkylidene benzo[b]thiophenes 187 with allenoates 188 (Scheme 46d) [94]. By the use of quinidine Cat-16 as catalyst and 2,4-dinitrobenzoic acid (2,4-DNBA) as additive, benzo[b]thiophene derivatives 189 and 190 were produced in high yields and high enantioselectivities.

    Scheme 46

    Scheme 46.  Research on the reaction of thioaurones with allenoic acid esters.
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    In 2019, our group explored the piperidine-catalyzed reaction of thioaurones 156 and nitrile compounds 191 at room temperature to form benzo[b]thiophene-fused pyran derivatives 192 (Scheme 47) [95].

    Scheme 47

    Scheme 47.  Research on thioaurones and nitrile compounds.
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    In the same year, Albrecht and co-workers proposed the synthesis of benzo[b]thiophene-fused derivatives 195 through a hetero-Diels-Alder cycloaddition of thioaurones 156 with azlactones 193. Under the catalysis of N-methylmorpholine 194, a series of benzo[b]thiophene-fused derivatives 195 were obtained in moderate to good yields (Scheme 48) [96]. The reaction mechanism showed that azlactone 193 was first deprotonated by the Bronsted base catalyst and then underwent a Diels-Alder reaction with thioaurones 156 to generate intermediate B, which was followed by a ring-opening process to form intermediate C. Finally, intermediate C gave the target product 195 via an epimerization process.

    Scheme 48

    Scheme 48.  Synthesis of benzo[b]thiophene-fused derivatives via hetero-Diels-Alder cycloaddition.
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    In 2022, Yuan and co-workers developed a [4 + 2] cycloaddition of 1-thioaurones 156 with γ-deconjugated butanolides 196 or azlactones 193. A series of benzo[b]thiophene-fused δ-lactones (197 and 198) were obtained with excellent dr and high ee under the catalysis of Cat-17, and gram scale experimental results (70% yield, 87:13 dr and 99% ee) demonstrated the practicality of this reaction (Scheme 49) [97].

    Scheme 49

    Scheme 49.  Cat-17-catalyzed synthesis of benzo[b]thiophene-fused δ-lactones.
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    5. Synthesis of benzo[b]thiophene fused cyclic compounds from azadienes bearing a benzo[b]thiophene moiety and their analogues

    In 2019, Chen et al. disclosed the synthesis of benzothienopyridine derivative 201 by cyclization of 1-azadienes 199 and α-bromoacetate 200 in a [4 + 1 + 1] fashion (Scheme 50a) [98]. In the presence of DABCO and Cs2CO3, the reaction proceeded smoothly in CH3CN at 40 ℃ for 72 h to produce the expected benzothienopyridine derivatives. In the same year, Moreau et al. investigated the polycyclization of azadiene 199 with dienal 202 (Scheme 50b) [99]. The intricately fused hexacyclic unsaturated imine 203 was obtained in a highly diastereoselective manner by stirring HFIP in 37% HCl at room temperature. At the same time, a rearranged product 204 was also observed and further rationalized by DFT calculation.

    Scheme 50

    Scheme 50.  Synthesis of benzo[b]thiophene-fused nitrogen heterocycles.
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    In 2021, our group disclosed the [4 + 3] cyclization between azadienes 199 and isatin-derived α-(trifluoromethyl)imines 205 (Scheme 51) [100] by using DMAP as the catalyst in CH3CN at 20 ℃. The condensed compounds 206 with a benzo[b]thiophene aza seven-membered ring were obtained.

    Scheme 51

    Scheme 51.  The [4 + 3] cyclization of azadienes with indoloisatinimines.
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    In 2020, Chen et al. investigated the asymmetric regioselective [4 + 3] cyclization of azadienes 199 with isatin-derived MBH carbonates 207 by a chiral catalyst (Scheme 52a) [101]. Under the catalysis of Cat-18, simultaneously at 4 Å MS in the presence of toluene, the reaction took place at room temperature to furnish the chiral azepanespirooxindole compounds 208 in high yields and excellent enantioselectivities. In 2021, Chen's group turned to study the [4 + 1] cyclization of azadienes 199 with trifluoromethyl ketone and acrylonitrile derived MBH carbonates 209 under amine catalyst (Scheme 52b) [102]. With the use of the tertiary amine chiral catalyst Cat-19, the expected products 210 were obtained in good yields and excellent enantioselectivities at −10 ℃ to room temperature in toluene solution in the presence of 4 Å MS. In the same year, our group also carried out the switchable domino reaction of azadienes 199 and isatin-derived MBH carbonates 211 under catalyst-control condition (Scheme 52c) [103]. The [4 + 1] cyclization was initiated in CH3CN at 67 ℃ using DABCO as the catalyst. The benzo[b]thiophene fused pyrrole derivatives 212 were obtained in moderate yields and higher dr values. The [4 + 3] cyclization was also initiated under the catalysis of DMAP in DMF at 67 ℃ to give benzothienoazepine derivatives 213.

    Scheme 52

    Scheme 52.  Cyclizations of azadienes and MBH carbonates.
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    In 2013, Chen et al. investigated the asymmetric cyclization of 1-azadiene 199 with cyclobutanone 214 (Scheme 53a) [104]. 4 Å MS was added in toluene solvent at 50 ℃ under the catalysis of Cat-20 modified cinchona alkaloids. The benzo[b]thiophene-fused eight-membered structure 215 was successfully constructed in good yields and remarkable enantioselectivities. Chen's group further studied the reaction of 1-azadiene in 2020. Under the catalysis of the chiral amine catalyst Cat-21 and in the presence of 20% mol benzoic acid solution, 1-azadiene 199 underwent an asymmetric Michael addition with arylaldehyde 216 (Scheme 53b) [105]. The γ-regioselective products 217 were isolated in excellent yields with high diastereoselectivities and enantioselectivities. Then, under catalysis of diethyl azodicarboxylate (DEAD) and PPh3 in 0.1 mol/L THF solution environment, the eight-membered ring benzo[b]thiophene fused derivative 218a was obtained in a satisfactory yield and high enantioselectivity.

    Scheme 53

    Scheme 53.  Synthesis of benzo[b]thiophene fused eight-membered ring compounds from azadienes.
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    6. Conclusions

    Sulfur-containing organic compounds, especially those bearing a benzo[b]thiophene skeleton, play a vital role in organic photoelectric chemistry and biologically active compounds. The past decade has witnessed the rapid development in the construction of these skeletons. This review summarized a series of efficient reactions reported in recent years for the synthesis of benzo[b]thiophene-fused compounds from thioaurone, thioisatin, substituted benzo[b]thiophene, and azadiene. A few of these reactions were developed by our group. Despite the progress achieved in this field, some problems remained to be unsolved: (1) The role of sulfur atom in governing the reactivity and/or selectivity has not been deeply understood until now. (2) Efficient strategies for the preparation of sulfur-containing π-extended polyaromatic hydrocarbons need to be broadened. (3) From the perspective of sustainable chemistry, green and economical strategies for the synthesis of benzo[b]thiophene fused compounds have been relatively deficient. (4) The applications of benzo[b]thiophene fused compounds are relative limited. Hence, it is still demanded to further develop new strategies to construct benzothiophene fused heterocycles. Firstly, the mechanism and origin of the special effects of sulfur atom need to be clarified to rationally control the expected reactivity and/or selectivity. Secondly, more efficient and greener strategies for the preparation of valuable benzo[b]thiophene fused compounds need to be exploited. Thirdly, we need to broaden the scope of potential applications of benzo[b]thiophene fused compounds to other areas. We hope this review will draw attention of chemists to achieve more advances on the construction of benzo[b]thiophene fused heterocycles in future.

    Declaration of competing interest

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    Acknowledgments

    This work was financially supported by the National Natural Science Foundation of China (Nos. 21403154 and 22003045), the Natural Science Foundation of Tianjin (No. 13JCYBJC38700), the Tianjin Municipal Education Commission (No. 2018KJ137).


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  • Figure 1  Pharmaceuticals and bioactive molecules containing benzo[b]thiophene scaffolds.

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    Scheme 1  Classic pathways for the synthesis of benzo[b]thiophene fused cyclic compounds.

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    Scheme 2  Synthesis of cyclopentannulated benzo[b]thiophenes by solvent-free domino reaction.

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    Scheme 3  The dearomative reaction of benzo[b]thiophenes.

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    Scheme 4  Ph2PMe-catalyzed reaction of nitrobenzo[b]thiophenes and allenoates.

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    Scheme 5  The [3 + 2] reaction of nitrobenzo[b]thiophenes and azomethine ylides.

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    Scheme 6  Organocatalytic asymmetric dearomatization reaction of 3-nitroindoles and 3-nitrobenzo[b]thiophenes with ethyl 4-mercapto-2-butenoate respectively.

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    Scheme 7  The metal-free one-pot reaction of 3-nitrobenzo[b]thiophenes and various phenols.

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    Scheme 8  Synthesis of benzo[b]thiophene-annulated heterocycles from substituted benzo[b]thiophenes and 2,5-dimethoxytetrahydrofuran.

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    Scheme 9  Synthesis of fused benzo[b]thiophene derivatives via Diels-Alder reaction.

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    Scheme 10  Synthesis of dibenzo[b,d]thiophene derivatives via Diels-Alder reaction.

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    Scheme 11  Synthesis of heterocyclic fused compounds by aza-Michael/Michael addition cascade reaction.

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    Scheme 12  Synthesis of benzo[b]thiophene-fused derivatives from benzo[b]thiophene derivatives and 2, 4-dienals derivatives.

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    Scheme 13  Synthesis of tetrahydrodibenzo[b]thiophene derivatives from benzo[b]thiophene-3-carbaldehydes and nitroolefins.

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    Scheme 14  Synthesis of benzo[b]thiophene-fused derivatives via NHC catalysis.

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    Scheme 15  Pd-catalyzed cyclization of benzo[b]thiophenes with 9,9-dimethyldibenzosiloles.

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    Scheme 16  Pd-catalyzed synthesis of benzothienopyridines.

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    Scheme 17  Rh-catalyzed annulation reaction of benzo[b]thiophenes with naphthalene derivatives.

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    Scheme 18  Rh-catalyzed cascade annulation of phenacyl phosphoniums and benzo[b]thiophenes.

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    Scheme 19  Iridium-catalyzed oxidative cyclization of phenylglyoxylic acids with benzo[b]thiophenes.

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    Scheme 20  Synthesis of benzo[b]thiophene-fused derivatives via Iridium catalysis.

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    Scheme 21  Synthesis of benzo[b]thiophene derivatives via [4 + 2] annulation.

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    Scheme 22  Phosphine-catalyzed [4 + 2] annulation of 3-nitrobenzo[b]thiophene with allenoates.

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    Scheme 23  Synthesis of benzo[b]thiophene-fused bicyclo[3.2.1]octa-2,6-dienes.

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    Scheme 24  Synthesis of benzo[b]thiophene-fused derivatives via [3 + 3] cycloaddition.

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    Scheme 25  The synthetic route for the preparation of benzo[4,5]thieno[2,3-b]indole derivatives.

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    Scheme 26  The synthesis of benzo[b]thiophene-fused 6- or 7-membered ring compounds.

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    Scheme 27  Synthesis of benzo[b]thiophene derivatives by palladium-catalyzed coupling reaction.

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    Scheme 28  Rh-catalyzed synthesis of benzo[b]thiophene-fused derivatives.

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    Scheme 29  Rh-catalyzed reaction leading to polycyclic benzo[b]thiophene-fused derivatives.

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    Scheme 30  Synthesis of benzothieno[3,2-b]furan-fused heterocycles via intramolecular C−O Ullmann reaction.

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    Scheme 31  Dehydrogenative cyclization of benzo[b]thiophene derivatives.

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    Scheme 32  PCy3-catalyzed intramolecular hydroalkylation of benzo[b]thiophen-3-ynones.

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    Scheme 33  Synthesis of [1]benzothieno[3,2-b][1]benzo[b]thiophene derivatives.

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    Scheme 34  The three-component reaction of 3-nitrobenzo[b]thiophene, cyclohexanones, and primary amines.

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    Scheme 35  Synthesis of tetralone derivatives via ring expansion reactions.

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    Scheme 36  Synthesis of benzo[b]thiophene-fused pyrrolidone derivatives by three-component domino reaction.

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    Scheme 37  Synthesis of benzothiopheno[2,3-e]azepinedione derivatives by three-component reaction.

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    Scheme 38  Synthesis of benzo[b]thiophene fused N-heterocycles by three-component domino reaction.

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    Scheme 39  Synthetic route to benzo[b]thiophene-fused polycyclic compounds and benzo[b]thiophene-fused eight-membered N-heterocycles.

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    Scheme 40  Approach to the synthesis of benzo[b]thiophene-fused heterocyclic derivatives.

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    Scheme 41  The domino reaction between thioisatins and α-bromoketones.

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    Scheme 42  The cycloaddition of thiouranone to dienamines.

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    Scheme 43  Cyclization of thioherones with allyl thiylides on different carbon atoms.

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    Scheme 44  Research on thiourea ketones and allyl phosphorus ylides.

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    Scheme 45  Research on the correlation between thiourea ketones and MBH carbonates.

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    Scheme 46  Research on the reaction of thioaurones with allenoic acid esters.

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    Scheme 47  Research on thioaurones and nitrile compounds.

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    Scheme 48  Synthesis of benzo[b]thiophene-fused derivatives via hetero-Diels-Alder cycloaddition.

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    Scheme 49  Cat-17-catalyzed synthesis of benzo[b]thiophene-fused δ-lactones.

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    Scheme 50  Synthesis of benzo[b]thiophene-fused nitrogen heterocycles.

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    Scheme 51  The [4 + 3] cyclization of azadienes with indoloisatinimines.

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    Scheme 52  Cyclizations of azadienes and MBH carbonates.

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    Scheme 53  Synthesis of benzo[b]thiophene fused eight-membered ring compounds from azadienes.

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文章相关
  • 发布日期:  2023-06-15
  • 收稿日期:  2022-09-22
  • 接受日期:  2022-11-10
  • 修回日期:  2022-11-03
  • 网络出版日期:  2022-11-13
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