Recent advances in the synthesis of thienoindole analogs and their diverse applications

Thiophene-fused heterocyclic organosulfur systems, especially the thieno[3,2-b]indole moiety have attracted significant attention because they show a wide spectrum of biological activities such as antituberculosis, antitumor, antifungal, antibacterial, and human 5-HT5A receptor binding inhibition. Moreover, they also find applications in material chemistry and chemical engineering. Thus, due to their intriguing properties and applications, researchers are continually attempting to create more effective and environment-friendly methods for their preparation. In this review, we present a complete assessment of the current advances in the field of thieno[3,2-b]indole synthesis.


Introduction
Thiophene-fused heterocyclic organosulfur systems have piqued the interest of chemists around the world as they exhibit a diverse set of biological properties and are considered safe compounds for agricultural and pharmaceutical applications. 1 The thieno [3,2-b]indole moiety is specically useful in the development of antituberculosis, 2 human 5-HT5A receptor binding inhibition, antitumor, 3 anti-infective, anti-osteoarthritis, 4 antibacterial, 5 and antifungal 6 drugs and also potent in curing neurological diseases such as senile dementia and Parkinson's disease (Fig. 1).
Moreover, it is an important type of p-extended electron-rich system, which can be used for designing molecules for photosensitive and photovoltaic devices. In the past few years, it has also been widely used in designing and engineering fused molecules for organic electronic application, which basically works via the electron push-pull mechanism. This moiety is present in several functionalized organic dyes 7-9 such as MKZ-39 and DPP-r-TI, which is an effective photosensitizer for photothermal and photodynamic therapies and polymers 10,11 such as PTITBT, PTTICN, PTTIF, and PTTI (Fig. 2).
According to the fusion of the thiophene ring on the indole ring, thienoindole can be categorized into different types. It is a tricyclic heterocyclic compound in which a thiophene ring is fused to an indole ring having one nitrogen atom. The fusion

Synthesis of thienoindoles
In the past few decades, thiophene-fused indoles have gradually been established as a novel class of valuable compounds having intriguing chemical activities and distinct biological activities. Plant growth regulators are critically important for crop production in high yield and enhanced quality, and therefore many plant growth-regulating chemicals have been synthesized to yield good seedlings by promoting root elongation. Nowadays, synthetic chemicals are used at various stages of rice plant development. A streptomycete strain identied as Streptomyces albogriseolus MJ286-76F7 produces a novel active chemical named thienodolin, an alkaloid having a thienoindole skeleton, which exhibits growth-promoting and growth-inhibiting activities in rice seedlings. In 1950, P. A. S. Smith and co-workers reported the rst synthesis of 4H-thieno [3,2-b]indole 6 from the diazotization of o-nitroaniline 9 and thiophene 10 via the formation of 2-(2-nitrophenyl)thiophene 11 (Scheme 1a). Later, in 1960, Kobayashi et al. synthesized thieno [2,3-b]indoles 5, starting from 3-(2-oxo-2-phenylethyl)indolin-2-one 12 and phosphorus pentasulde 13 (Scheme 1b). In the early 90 s, Nakamura et al. structurally elucidated and Kanbe et al. isolated and characterized thienodolin by actively extracting thienodolin from a Streptomyces albogriseolus culture broth using ethyl acetate as the solvent followed by purication via preparative HPLC and silica gel column chromatography. It was found that when rice seedlings were treated with 1.2 Â 10 À6 to 1.2 Â 10 À5 M thienodolin, it exhibited growth-promoting activity, whereas 4.0 Â 10 À5 M thienodolin showed inhibitory activity in rice seedlings.

Synthesis of thieno[2,3-b]indole by radical cyclization
Singh et al. 12 synthesized substituted thieno [2,3-b]indole 15 using the radical cyclization approach in 2011 (Scheme 2). However, although this is an effective approach for the synthesis of thieno [2,3-b]indole in high yield, the substrate, (obromoindolyl)acrylonitrile 14, used is synthesized in many steps via the base-induced condensation of (o-bromoindolyl) acrylonitrile with various aryl/heteroaryldithioesters. Also, the 1 H NMR spectrum of the substrate showed that the substrate is produced as an inseparable mixture of (E)/(Z) isomers. Moreover, the push-pull nature of the double bond forced the substrate to undergo thermal (Z)/(E) isomerization.
Thieno [2,3-b]indole and its derivatives were also prepared via the nitrene-mediated Cadogan cyclization of 3-(o-nitrophenyl)thiophene, AlCl 3 -induced electrophilic recyclization of 2-(2-furyl)aryl isothiocyanates and oxidative cyclization of indolin-2-thiones. However, most of these methods are afflicted by drawbacks of multistep precursor synthesis, limited scope and generality. Accordingly, considering their applications in pharmaceuticals and materials science, more versatile and effective strategies for the synthesis of thiophene-fused heterocycles are needed.

Synthesis of 2-substituted thieno[2,3-b]indoles by Lawesson's reagent (LR)
Igrashev and co-workers reported the convenient, short and reliable synthesis of 2-substituted thieno [2,3-b]indoles from readily available reagents involving the two-step reaction-aldolcrotonic condensation of the starting materials and treatment of the intermediate with Lawesson's reagent. The reaction of the intermediate with LR takes place in two steps. Initially, the ethylidene double bond of indolin-2-ones undergoes reduction, and then Paal-Knorr cyclization occurs to give the tricyclic product.
When isatins 16 are treated with methyl ketones 17 in mild base, e.g., secondary and tertiary amines, aldol-type adduct 18 is formed, which undergoes dehydration under acidic conditions to form the crotonic condensation product 3-(2-oxo-2-(hetero) arylethylidene)indolin-2-one 19. Compound 19 is more stable than compound 18 given that compound 19 is an unsaturated 1,4-diketone. The carbon-carbon double bond of 19 undergoes reduction in the presence of Na 2 S 2 O 4 , 13 H 2 /Pd(C) 14 or Me 3 P-H 2 O (ref. 15) (Scheme 3) to give indolin-2-one 20. Compound 20, which bears a 4-oxobutyramide fragment (1,4-dicarbonyl derivatives), undergoes Paal-Knorr reaction in the presence of thionation agents such as P 4 S 10 or Lawesson's reagent and gets cyclized into thieno [2,3- Depending on the reaction conditions, the Paal-Knorr reaction produces pyrroles, furans or thiophenes from 1,4diketones. Thiophene is obtained by using sulfurization agents such as phosphorus pentasulde and Lawesson's reagent. LR is used as a thiation agent and is a powerful dehydrator, driving the reaction towards completion. This reagent has a fourmembered ring of alternating phosphorus and sulfur atoms.
Although this synthetic strategy appears to be appropriate, it has little preparative interest given that thienoindoles are obtained in low yields. For example, 2-methyl-8H-thieno [2,3-b] indole was obtained in 15% yield via this four-step pathway using unsubstituted isatin and acetone.
This procedure was further modied using path A to path D to enhance the overall yield of the desired product. Thieno [2,3b]indole 21a was prepared using 1-ethyl-isatin 16a and acetophenone 17a in the presence of base and ethanol via path A to path D (Scheme 4).  2.2.1 Path A. Compound 18a was reuxed with LR in toluene for 1 h and the target compound 21a was obtained in very poor yield (10%).
2.2.2 Path B. This is the conventional path to get 19a via the dehydration of aldol adduct 18a. Further, the reduction of 19a generates indolin-2-ones 20a, which undergoes cyclization using LR to give substituted thienoindole 21a (25%).
2.2.3 Path C. This is a one-pot synthetic route, which involves the reaction of isatin 16a with (phenacylidene)triphenylphosphorane 22 to give intermediate 19a, which gets cyclized to give 54% of 21a. However, the limitation of this method is the use of phosphorane derivative 22 (formed by prefunctionalization of acetophenone 17a), which is very expensive.
2.2.4 Path D. This pathway involves the reuxing of intermediate 19a with LR in toluene for 1 h, giving 21a in 57% yield.
Lawesson's reagent rst acts as the source of H 2 S to reduce C]C in 19a, and then acts as the thiation agent to give 21a via Paal-Knorr reaction. Thus, the four-step procedure is reduced to a two-step procedure, leading to an overall good yield of the product. Hence, path D is the most effective, shortest and most robust method for the synthesis of thienoindoles. In some specic cases, path C is also used as an alternative synthetic route.

Synthesis of thienoindoles via
Pd-catalyzed cross coupling reaction 2.3.1 Pd-Catalyzed cross-coupling reactions. Palladium can transfer two electrons and form complexes in the 0 and +2 oxidation state. According to Pauling's scale, Pd has an electronegativity of 2.2, which leads to the formation of relatively stable and non-polar Pd-C bond. Thus, Pd is extensively used in synthesis. Due to the capacity of Pd to interact with non-polar bonds, a heteroatom a lone pair of electrons can easily undergo oxidative addition, transmetalation and reductive elimination. Heck, Negishi and Suzuki pioneered the work on Pd-catalyzed cross-coupling reactions and were awarded the Nobel prize in 2010.  2.3.2 Suzuki-Miyaura cross-coupling reaction. The Suzuki-Miyaura reaction is a coupling reaction between aryl halides and organoborane reagents, including boranes, boronic acids and boronic esters. Organoboranes are non-toxic, air and moisture resistant and can be easily handled. The non-polar nature of the C-B bond (because of the relatively lower electronegativity of boron) makes it more stable than other metalcarbon bonds such as Li, Mg, Si, Al, Zr, Cu and Sn.
2.3.2.1 Role of base and solvent. In most organoboron compounds, the C-B bond is extremely covalent and the complex does not undergo transmetalation easily. Thus, the notable and signicant role of the base such as K 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , NaOH and NaHCO 3 in the Suzuki-Miyaura reaction is to activate the organoboron derivative by making a hypervalent, anionic boron-"ate" complex, which promptly undergoes transmetalation. In an alternative process, the base displaces the halide in the [PdXR 2 ] complex to form the [Pd(OtBu)R 2 ] complex (Scheme 5).
The activity and selectivity of the Suzuki-Miyaura reaction are inuenced by the solvent such as PhMe, DMF, 1,4-dioxane, benzene, THF and CH 3 CN. Moreover, a mixture of organic solvents and water can be utilized to increase the rate, selectivity and yield of the coupled product. In the current scenario of synthesis, a mixture of toluene and 1,4-dioxane is used as the organic solvent and water as the co-solvent.
2.3.3 Buchwald-Hartwig amination reaction. A Pd catalyzed cross-coupling reaction between amines and aryl halides forms the C-N bond. In the case of P(t-Bu) 3 , a monodentate ligand, the active Pd[P(t-Bu) 3 ] is formed. Imine is obtained as a by-product due to the b-hydride elimination reaction, which occurs when the H-atom is at the a-position to the N-atom.
Toluene and 1,4-dioxane are frequently used as solvents given that they have a high boiling point and can solubilize most organic compounds. Generally, strong bases such as NaOtBu and KOtBu in toluene are used to increase the reaction rate and product yield.   were rstly synthesized in 1982 via two methods (Scheme 6), as follows: (a) Reaction of substituted indole with thioamide. 16 (b) Reaction of 3-hydroxy thiophene with hydrazine. 2 However, these methods were tedious, inexible and no improvement was reported until 2000. Later, the development of Pd cross-coupling chemistry facilitated the synthesis of thienoindoles and a palladium-catalyzed two step procedure has been developed, which involves a Suzuki reaction to form a C-C bond between benzene and thiophene, followed by ring closure. Ring closure reaction can be of three types, as follows: (a) nitrene insertion, 17 (b) oxidative C-N coupling 18 and (c) Cadogan cyclization. 19 Thieno[3,2-b]indoles were synthesized efficiently via the siteselective Suzuki-Miyaura coupling of 2,3-dibromothiophene with 2-bromophenylboronic acid, 20 and subsequent two-fold palladium catalyzed C-N coupling (Buchwald-Hartwig reaction). In the rst step, 2,3-dibromothiophene 23 is converted to 3bromo-2-(2-bromophenyl)thiophene 24 in 82% yield (Scheme 7).
In conclusion, thieno[3,2-b]indoles and thieno [3,4-b]indoles have been synthesized via a new, more efficient and convenient synthetic methodology, namely, Buchwald-Hartwig crosscoupling. Also, the role of the ligand was found to be more crucial in the second step.

Synthesis of thieno[3,2-b]indole via Cadogan reductive cyclization
Dehaen et al. 19 synthesized thieno [3,2-b]indole in two steps. The rst step is the Suzuki-Miyaura coupling reaction between onitrophenyl boronic acid 34 and 2-bromothiophene 35. The recent literature revealed that arylboronic acids substituted with electron-withdrawing groups (here, nitro at the ortho position) undergo extensive deboronation under standard Suzuki-Miyaura conditions, which employ aq. Na 2 CO 3 as the base. This premature destruction of the C-B bond causes low yields. Hence, to reduce or protect from proto-deboronation, Suzuki-Miyaura coupling reaction has been performed under microwave-enhanced conditions. The second step is the nitrene-mediated reductive cyclization of 2-(2-nitrophenyl) thiophene 36 under MW irradiation, which leads to a dramatic rate enhancement given that the usual method demands drastic conditions and long reaction time (Scheme 13).   Further, a mixture of compound 36 and triethyl phosphite was suspended in a 10 mL sealed glass vial and irradiated with 300 W power at 210 C. Bunyan and Cadogan demonstrated that aromatic C-nitroso-compounds are promptly deoxygenated by triethyl phosphite. Hence, deoxygenation of 36 led to the formation of a nitroso-compound, which readily underwent deoxygenation, resulting in the formation of an indole ring via a nitrene intermediate. 23 The reaction took 15 min to go to completion and acidic work-up removed the phosphate byproducts and product 37 was obtained in good yield (Scheme 14).
Dehaen et al. used 2-nitro-phenylboronic acid given that it gives access to the biaryl compounds needed for the Cadogan cyclization and also heterocyclic boronic acids are expensive and difficult to synthesize. Hence, it is a more versatile, efficient and economic method for synthesizing thieno[3,2-b]indoles.

Metal-free approach for synthesizing regioselective thieno[2,3-b]indole
Penghui et al. 24 described an effective metal-free approach for synthesizing substituted thieno[2,3-b]indole 40 and 41 with high regioselectivity and great functional group tolerance. In this approach, the cascade cyclization occurs via the acidpromoted annulation of ketone 38, indole 39 and sulfur powder, where the solvent DMF and the additive control the regioselectivity of the reaction (Scheme 15).
2.5.1 Multi-component reactions. Multicomponent reactions are very efficient given that they are an easy and atomeconomic approach, which is highly advantageous compared to the conventional methods of synthesis. In this process, more than two starting materials combine to form a product, which contains almost all the employed atoms. MCRs can be divided into three types, i.e., domino or cascade, sequential and consecutive MCR. Domino reactions take place without the requirement of additional reagents or without the need for changing the reaction conditions, i.e., everything needed for the reaction is there at the beginning. In the case of sequential MCR, the functionality necessary for the second step is created in the rst step but an additional reagent must be added for the second reaction to occur. In consecutive MCR, the subsequent addition of reagent is done together with changing the reaction conditions from one step to another. Each type of MCR provides high structural and functional diversity. 25,26 Elemental sulfur was used as the source of sulfur given that it is abundant in nature, non-toxic and stable under normal conditions. Its low price and high purity make it a good choice. In recent years, elemental sulfur had found great applications in C-S bond-forming reactions. Most of the reported C-S bond formation reactions using elemental sulfur are catalyzed by transition metals. However, a few reactions are also available that do not need any transition metal. 27 Our reaction is among these types of reactions (Scheme 16).
1-Methyl-1H-indole 39, acetophenone 38 and sulfur powder were reacted using different additives and solvents. The desired product, i.e., 3-phenylthieno[2,3-b]indole 40 was obtained when chlorobenzene was used as the solvent and 50 mol% HI as an additive at 130 C. Further, the yield of product 40 was improved using PhCF 3 and anisole as additives and 1,4-dioxane as the solvent. The yield of 40 was further improved using PhCF 3 /1,4dioxane, which was further greatly enhanced when 1 equivalent of L-phenylalanine was used together with PhCF 3 and 1,4dioxane. 2-Phenylthieno[2,3-b]indole 41 was obtained when DMF was chosen as the solvent, whose yield was increased when acetic acid was used as the acid instead of HI. This is because when DMF was used as the solvent, the regioselectivity of the cyclization process switches as a result of the change in the polarity of solvent. This is a direct cyclization reaction. The reaction yield of 41 and the ratio of 41 : 40 further increased when the temperature was increased to 150 C and the ratio of 39 : 38 changed to 1 : 2.3.
Further, the yield of product 44 was affected by the position of the functional group on the indole ring. When it was present on C-5, C-6 and C-7, then the yield of the product was good, whereas when it was present at the C-4 position, the yield decreased dramatically (Scheme 18). Further, indoles bearing various substituents gave the product in a yield of up to 83%. When Me was at the C-6 or C-7 position of the indole moiety, the yield of product 45 decreased slightly to 67% and 73%, respectively, as shown in Scheme 20.  Li et al. 31 synthesized thieno [2,3-b]indole from indoles and alkenes or alkynes in the presence of sulfur powder and in the absence of metal. This is a simple and efficient method in which a Brønsted acid promotes the formation of substituted thieno [2,3-b]indole, where DMF is essential for converting the reactants into the fused products. Substituted 1-methylindole 39a, substituted alkyne 50 and sulfur powder were treated in acid at 150 C and in metal-free conditions using DMF as a solvent to obtain product 51. However, in the absence of DMF, no product was obtained (Scheme 23).
Further, product 41 was obtained in 70% yield when AcOH was used as an acid. Moreover, inorganic acids such as hydrochloric acid acted as the most efficient acid and gave the product in 86% yield. Reducing either the reaction temperature or HCl concentration reduced the yield of the product (Scheme 24).
2.6.1 Substrate scope for the formation of substituted thieno [2,3-b]indole. The yield of the product depends on the substrate used (Scheme 25).
Further, different substituted indoles 39a were reacted with phenylacetylene 52 and sulfur powder and the product was  The reactions of substituted indoles 39a such as methyl, methoxy, bromo, uoro and chloro gave the product in good yield independent of the position of the substituent at the C-5, C-6 or C-7 position. Even good yield of the product was obtained when unprotected indole was used as the substrate (54-79%, Scheme 28).

Preparation of thieno[3,2-b]indole by halogen dance and sequential coupling reaction
The favourable environment for halogen dance with 2,5dibromothiophene 57 occurred by its deprotonation at the 4position with 1.3 eq. LDA at À78 C for 5 min. 37 Moreover, the lithiated species gets rearranged to 5-lithio-4-brominated thiophene 58 at À78 C via halogen dance, which on treatment with ZnCl 2 in tetramethylethylenediamine 38 (TMEDA 1.4 equiv.) at 0 C formed thienylzinc species 58a, which was further subjected to coupling conditions using the transition metal catalyst Pd(PPh 3 ) 4 and protected iodoaniline at 60 C for 24 h, forming the coupled product 59 in 69% yield (Scheme 30).
Hayashi et al. 34  The above-mentioned reaction failed in the absence of additive, as reported by Okano and coworkers, 44 demonstrating that the additive plays an important role in signicant amination for getting the desired product. Despite the longer response time of 24 h at 125 C, additives such as NaOtBu were detected to be insufficient. The addition of tBu 3 P$HBF 4 (20 mol%) notably promoted amination to form 4-phenyl-2-(p-tolyl)-4Hthieno [3,2-b]indole 61 in 69% yield. A reduced amount of the phosphorus ligand in the additive led to a lower yield of 61. This outcome suggests that tBu 3 P, a monodentate ligand, needs to coordinate Pd with dppf, a bidentate ligand to form the efficient catalyst in situ for intramolecular amination (Scheme 32).
The one-pot reaction was also reported at 125 C for 5 h by one-shot addition, which included all the required reagents for forming aryl substituted thieno [3,2- mentioned reaction conditions (Scheme 20) were not applicable for Ar ¼ 4-nitrophenylboronic acid given that it has low solubility in 1,4-dioxane, and thus water as the co-solvent in a ratio of 4 : 1 mainly helps to maximize the yield of 2-(2-nitrophenyl)-4-phenyl-4H-thieno [3,2- The Pd-dppf catalyst plays an important role in Suzuki-Miyaura coupling, which led to C-C bond formation at the aposition of thiophene by releasing the bromo group. Further, ligands were exchanged from Pd-dppf to Pd-(tBu 3 P) 2 and the reaction moves towards C-N bond formation in which the bbromo group undergoes oxidative addition of the Pd-(tBu 3 P) 2 catalyst and reductive elimination to yield 4-phenyl-2-(aryl)-4Hthieno[3,2-b]indole 61. The maximum yield was obtained when tBu 3 P was used as an additive for amination. The following sequential coupling reactions (Scheme 34) were reported as tandem catalytic pathways. 3(2H)-one was acquired in two steps, i.e., the reaction of abromocinnamates or their other hetero derivatives with methyl thioglycolate, followed by the base treatment of 5-(hetero)aryl-3hydroxysubstituted 2-thenoates to yield 2-(hetero)arylsubstituted thieno [3,2-b]indole.
Convenient and cheap synthetic approaches are urgent to meet the growing demand of hetero-arylated thieno [3,2-b] indoles, which are widely used in optoelectronic material engineering. In this context, the retro-synthetic approach towards the synthesis of thienoindoles is shown in the following scheme (Scheme 35).
Various organic and inorganic bases were tested as substitutes for KOAc to get the product in higher yield. Among them, K 2 CO 3 , NaOH, Cs 2 CO 3 (inorganic bases) and Et 3 N (organic base) in the presence of CH 3 CN resulted in the formation of dihydrothienoindole 80a (Scheme 28), which was nally converted to thieno [2,3-b]indole derivative 80 (Scheme 41).
In the synthesis of thieno-[2,3-b]indole via MBH reaction, rstly proton abstraction at the C-3 position of indoline-2thione 79 takes place to form an anion, which attacks hydrazinonitroalkene 76 via Michael addition reaction to form an intermediate that is further activated by the H-bonding property of acetic acid to form 81a. Subsequently, the removal of the nitro group was facilitated by the lone pair of the hydrazine moiety and an acyl iminium-type intermediate 81b was generated. Following this, intramolecular 5-exo-trig cyclization of 80 occurred to form dihydrothienoindole 81c, which underwent aerial oxidation to give aromatized thienoindole 80. The reaction can also occur in a different manner, where thio-enolization of 81a takes place initially, and then intramolecular 5-exo-tet cyclization and aerial oxidation takes place to form thieno [2,3-b]indole 80 (Scheme 42).
The presence of electron-donating groups on the aryl ring of RC-adduct 78 signicantly reduced the product (82b and 82c) yield with respect to 82a (Scheme 40, Fig. 8).
(1) Presence of numerous electron-donating groups at several positions resulted in good yield of products 82d and 82e.
(2) Presence of weak electron-withdrawing group such as 4chloro-substituted RC-adduct 82f led to moderate yield (63%) of the product (Fig. 9).  Several N-protecting groups such as ethyl and benzyl resulted in excellent yield of thieno [2,3-b]indole derivatives 82g and 82k, whereas groups such as H and n-propyl led to a much lower yield of derivatives 82h and 82m (Fig. 9).
The base-directed Michael addition of indoline-2-thione 79 to RC-adduct 78-formed intermediate 83a and intramolecular thio-Mannich-type reaction in 5-exo-trig fashion led to intermediate 83b, and further removal of HNO and H 2 O gave the aromatized product. The overall mechanism involved in the synthesis of the thienoindole derivative is depicted in Scheme 44.

Synthesis of thieno[3,2-b]indole derivative via in situ generation of 3-aminothiophene
It is a convenient method to synthesize thieno [3,2-b]indole having a thien-2-yl, aromatic or styryl group at the C-2 position. This method uses 5-substituted-3-aminothiophene-2carboxylate and proceeds via Fischer indolization. It involves two steps, where the rst step is the saponication of 3-aminoester with NaOH, and in the second step, this sodium salt reacts with arylhydrazine in glacial CH 3 COOH. In the latter step, decarboxylation of 3-aminothiophene-2-carboxylic acid takes place to give 3-aminothiophene, which further reacts with arylhydrazines under acidic conditions to form arylhydrazone, ultimately undergoing Fischer indolization to give the desired product 58 73.
Thiophene derivatives with an amino group at the C-3 or C-3 and C-4 position have found numerous applications in the formation of thiophene-fused N-heterocycles such as thienoindoles. 59 2.10.1 Similarity in the behaviour of 3-aminothiophene and thiophene-3(2H)-one. 3-Aminothiophene can be considered the synthetic counterpart of thiophene-3(2H)-one 85a for annulation reactions. It has been observed that the 3-aminothiophene moiety shows an enamine nature and its protonation takes place on the C-2 position, thereby forming thiophene-3(2H)-iminium cation 60 84, which can further react with the nucleophile at the C-3 position to give 85 (Scheme 45).  Later, they described another method for the synthesis of 2substituted thieno [3,2-b]indoles starting from 5-substitutedmethyl-3-aminothiophene-2-carboxylates 87 via the in situ generation of 3-aminothiophene, which further participates in Fischer indolization with arylhydrazines (Scheme 47).
In the earlier method for the preparation of thieno[3,2-b] indole, DMSO was used for the saponication of 3-  hydroxythiophene-2-carboxylate. However, the problem was the high temperature required for the reaction due to the initial occurrence of sodium-2-(methoxycarbonyl)thiophen-3-olate. Therefore, the direct conversion of 3-aminothiophene-2-carboxylate was carried out using NaOH in aqueous i-PrOH, without the isolation of the intermediate formed, 3aminothiophene.

Metal-free synthesis of thieno[2,3-b]indoles using elemental sulfur
Thieno[2,3-b]indoles have been synthesized via a base-assisted metal-free approach using cheap and readily available elemental sulfur. 67 The development of attractive and valuable routes for forming carbonyl group-containing thieno [2,3-b] indoles represents several challenges. Here, b-indolyl ketone derivatives were used as effective and easily accessible substrates for the synthesis of carbonyl group-containing thieno [2,3-b]indoles through a C]S bond formation reaction.
3-(1H-indol-3-yl)-3-phenyl-1-(o-tolyl)-propan-1-one 94 treated with elemental sulfur and base NaOtBu using anhydrous DMSO as the solvent at 120 C under N 2 for 24 h gave product 99 in 97% yield. Moreover, other organic bases, e.g., DBU, gave the product in a minute amount, whereas DABCO yielded the nal product in 90%. The quantity of elemental sulfur did not affect the yield of the product 68 (Scheme 50).
Moreover, the yield of the product decreased when an electron-withdrawing group was substituted at the p-position of an extra benzene ring (99a, Fig. 10) and increased in the case of an electron-donating group (99b, Fig. 10).
Furthermore, the presence of methyl, chloride, phenyl and nitrile groups at the p-position of the aromatic ring substituted at the C-3 position of the thienoindole derivative resulted in Fig. 12 Examples of thienoindole analogs having biological activity.   a high yield of the corresponding derivative products 99c-99f (Fig. 11). The reaction was conducted in the presence of economical and widely accessible reagents, i.e., sulfur, acetophenone 38 and indole 39a, using the magnetic recyclable nanoparticle DES@MNP catalyst in N,N-dimethylformamide at 140 C for 12 h. The deep eutectic solvent was prepared with 1.2 g urea in 0.68 g zinc chloride at 100 C and further mixed with silicacoated Fe 3 O 4 nanoparticles at 100 C for 18 h and dried under low pressure at 60 C for 6 h to form the DES@MNP catalyst. The deep eutectic solvent-covered nanoparticles were benecial for easy handling, separation and recycling. Moreover, the magnetic nanoparticles have the advantages of easy preparation, high stability, low cost, availability, high surface area and easy separation by a magnet for reuse (Scheme 52).
The proposed mechanism for the synthesis of thieno[2,3-b] indole from acetophenone 38, N,N-dimethylformamide and sulfur aided by the DES@MNP catalyst suggests that the reaction takes place through the formation of 1-(dimethylamino)-2phenyl-1H-thiiren-1-ium 47, which further forms 47a (65%).  a ring-opening addition mechanism, ring closure and elimination of dimethyl-amine to form 47 in 87% yield. Furthermore, indole reacts with the reaction mixture, forming 87% product. Moreover, the proposed research led to an efficient protocol having merits, which include simple and efficient recyclable heterogeneous catalyst, vast substrate scope and regioselective product in high yield (Scheme 53).
The alkaloid thienodolin 70 103 is a natural derivative of thieno [2,3-b]indole obtained by the fermentation mixture of Streptomyces albogriseolus (Fig. 13). Kanbe et al. characterized its activity for plant growth regulation. Furthermore, some thienoindoles are used to treat diseases of the central nervous system and some are potential inhibitors of acetylcholine esterase and butyrylcholine esterase.

Chemical activities of thienoindoles
Besides their therapeutic properties, thienoindoles are also used for designing molecules of photosensitive and photovoltaic devices because of their p-extended conjugation from electron-rich systems. They are reported to be effective photosensitizers for photothermal and photodynamic therapies and polymers such as PTTICN, PTTIF, and PTTI. Moreover, TI-DTBT3 104 is a donor-acceptor p-conjugated polymer with high charge carrier mobility. 71 This moiety is interestingly available in several organic dyes such as MKZ-40 105 and DPP-r-TI. They are also used as precursors of polymers used in solar cell applications (Fig. 14).

Electrical activities of thienoindoles
Derivatives of thieno [2,3-b]indole are used to design photo-and electroactive compounds, which have been recently assessed in dye-sensitized solar cells (DSSCs). Push-pull dyes IK-1,2 viz., 106 and 107 have been recently reported to be synthesized as a donor part of DSSCs 72 (Fig. 15).
MTI-DCV 113 is the smallest push-pull molecule of the series. It has a high absorption coefficient, high thermal stability, good hole transport properties and good absorption in the visible region, and because of all these properties, a bilayer solar cell mostly composed of MTI-DCV showed a power conversion efficiency of more than 1%.

Conclusions
Thieno [2,3-b]indole and thieno [3,2-b]indole molecules have been extensively studied because of their wide range of acceptable biological and pharmaceutical applications and other characteristic uses such as in photothermal and organic photovoltaic cells (OPV), making them valuable heterocycles in synthetic organic chemistry, materials chemistry and chemical engineering. Over time, researchers have overcome multiple problems associated with their synthesis such as tedious product separation, problematic catalyst recovery and need for large stoichiometric amounts of solvent. Moreover, the use of highly volatile, toxic and explosive substrates, solvents, and additives for the preparation of thiophene-fused indoles limit their widespread application. Some synthetic protocols also use toxic and corrosive bases such as DABCO, DBU, and LDA and hazardous solvents such as 1,4-dioxane and DMF for the synthesis of thienoindoles. Moreover, a few of the reported methods for their synthesis require the use of functionalized furans, indoles, thiophenes, etc. as precursors, which are synthesized via multiple steps, making them inefficient. Thus, to overcome the aforementioned issues, newer and convenient synthetic strategies need to be developed, which involve environment-friendly solvents such as water, ethanol, and PEG and reduction in the use of workup solvents. Further, the electronic push-pull mechanism and extended conjugation indicate that thieno [2,3-b]indole-based polymers and dyes that display a large variation in properties are still to be discovered. Finally, the future prospects in the arena of thieno [2,3-b]indoles synthesis depends on the progress of competent synthetic procedures that can solve the above-mentioned concerns, while keeping environmental-friendliness a priority.

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