Benzothiazoles from Condensation of o-Aminothiophenoles with Carboxylic Acids and Their Derivatives: A Review

Nowadays, organic chemists are interested in the field of heterocyclic chemistry due to its use in the synthesis of a great variety of biologically active compounds. Heterocyclic compounds are widely found in nature and are essential for life. Among these, some natural nitrogen containing heterocyclic compounds have been used as chemotherapeutic agents. Their attachment to sugar molecules either as thioglycosides or as nucleosides analogues plays an important role in vital biological processes as well as in synthetic organic chemistry. Molecules containing benzothiazole (BT) nuclei are of this interesting class of compounds because some of them have been found to have a wide variety of biological activities. In this sense, we selected this topic to review and to then summarize the procedures related to the condensation reactions of o-aminothiophenoles (ATPs) as well as their disulfides with carboxylic acids, esters, orthoesters, acyl chlorides, amides, and nitriles. The condensation reactions with carbon dioxide (CO2) are included. Conventional methods with the use of acid and metal catalysts as well as recent green techniques, such as microwave irradiation, the use of ionic liquids, and ultrasound (US) chemistry, which have proven to have many advantages, were found in the review.


Introduction
Benzothiazole (BT) belongs to the family of benzazole compounds. The base structure of BT consists of a benzene ring fused with the 4 and 5 positions of a thiazole ring. These two rings together constitute the bases of the planar structure of the BT nucleus. BT is a colorless and slightly viscous liquid compound with a molecular formula C 7 H 5 NS. This is considered as a weak base with a melting point of 2.0 • C, a boiling point of 227-228 • C, a density of 1.24 g/mol, and a molecular mass of 135.19 g/mol. This privileged bicyclic ring system has been found in various natural compounds, which have a wide range of pharmaceutical applications [1][2][3]. Scientists have discovered the BT nucleus in natural products such as bisabolane-type sesquiterpenoid from the roots of Ligularia dentate (compositae) and diterpenes erythrazoles A and B of mangrove sediments ( Figure 1) [4,5].
The studies of structure-activity relationship (SAR) of BTs have revealed that a change in the structure of the substituent group at the C2 position, in general, changes the bioactivity. Therefore, the biological profiles of this compound encourages researchers to design novel and efficient methods for the synthesis of BTs and their structural analogues. The development of these synthetic processes is undoubtedly one of the most significant challenges facing researchers.
Since the 2-substitutedBTs synthesized by A. W. Hofmann in 1887, organic chemists have developed synthetic processes to access BT compounds. Investigation into the synthesis of BT derivatives has been increasing over the years, and several reviews about this topic have been reported in the literature [81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96][96][97][98][99][100][101][102][103][104]. It is worth mentioning that at least eight reviews, performed in 2020 alone, have been found about the synthetic strategies and biological activities of BT nucleus derivatives [97][98][99][100][101][102][103][104]. In these works, we found that many protocols have been developed for the synthesis of BTs. However, only a few methods for the condensation of o-aminotiphenoles (ATPs) with carboxylic acids and their derivatives were discussed. Accordingly, in our article, we present a literature review on the aspects of the research progress related to the condensation of ATPs with carboxylic acids and their derivatives, such as acid chlorides, amides, esters, orthoesters, nitriles, and thioesters, including carbon dioxide (CO 2 ), as starting materials. This report includes protocols ranging from those for conventional methods, such as the use of heterogeneous solid acid catalysts and reactions performed under mild and solvent-free conditions, to those for green chemistry methods, such as the use of ionic liquids, reactions under microwave irradiation, as well as the use of ultrasound energy performed in the last 20 years.

Condensation with Carboxylic Acids
Considering a retro-synthetically point of view, a carbon-sulfur (C2-S) bond of 2-substitutedBTs 5 can be cleaved to represent an o-amidethiophenol 3, which can be obtained from the condensation of ATP 1 and a carboxylic acid 2 (Scheme 1). This approach proceeds with the intramolecular cyclization of the o-amidethiophenol 3 via the SH group by an oaryl-S cross-coupling protocol to the hydroxybenzothiazolidine ring 4, which on heating or catalytic dehydration, produces the corresponding benzothiazole derivative 5 (Scheme 1). Polyphosphoric acid (PPA) has been extensively used as a good solvent for many organic compounds in organic synthesis. It has been used as one of the most effective reagents for acylation, alkylation, cyclization, and acid-catalyzed reactions. It is often the reagent of choice for a variety of synthetic transformations, such as dehydrations, rearrangements, and synthesis of nitrogen-containing heterocycles. PPA has also proved to be very useful in polymer synthesis.
Hein et al. used PPA as a solvent, a catalyst, and a dehydration agent in the condensation of ATP with carboxylic acid, ester, amide, or nitrile to generate 2-arylBTs and 2-alkylBTs in good yields. This procedure gives products not obtainable by other procedures [105].
ATP and 2-picolinic acid were condensed in the presence of PPA while stirring at 120 • C under N 2 and then for 20 h at 160 • C. After separation and purification, the precipitate was recrystallized from methanol to afford 2-(o-pyridyl)BT 19a ( Figure 5) as a pale-yellow solid in a 45% yield (the table in Figure 5) [114]. Compound 19a was used as a bidentate ligand to afford a palladium (II) complex. Antibacterial activity of the ligand and the corresponding complex against three Gram − negative and two Gram-positive microorganisms was performed, and the complex showed better microbial inhibition activity than the ligand and the palladium salt as reference.   The condensation reactions of 4-amidino-substituted ATPs with 2,5-furan-and 2,5thiophene dicarboxylic acid were performed on heating in PPA at 180 • C for 2 h. The bisamidinodiBTyl compounds 24 and 25 were isolated as hydrochloride salts in 35-76% yields (Scheme 12) [117].

Scheme 12. Condensation to access Bisamidinobenzothiazoles as hydrochlorides.
A single-step method to synthesize 2-arylBTs 26 in 50-60% yields has been reported from the condensation of ATP with substituted p-aminobenzoic acids in the presence of PPA on heating at 220 • C for 3 h (Scheme 13) [118]. To improve the yield, 4-nitrobenzoic acid was condensed on heating at 180 • C for 5 h to afford 2-(p-nitrophenyl)BT in an 81% yield, with subsequent reduction using Fe/NH 4 Cl in refluxing 75% ethanol for 2 h, which gave access to 2(p-aminophenyl)BT 26a (Scheme 13). The same reaction conditions were used in the condensation of ATP with p-nitrobenzoic acid and 4-aminobenzoic acid to produce the corresponding 2-(p-aminophenyl)BT in a 90% yield (Scheme 13) [119]. Isomeric-amidinoBTyl-disubstituted pyridines 27a-i and pyrazine 28 were synthesized in 46-79% yields by the condensation reaction of pyridine and pyrazine dicarboxylic acids with 5-amidino-and 5-imidazolinyl-substituted ATPs. To improve yields, the quantity of the byproducts was reduced on heating in PPA first at 120-140 • C for 1 h and then for 2 h at 160-180 • C (Figure 7) [120]. In a method developed by Santos et al., ATP was condensed with amino acids, such as glycine and d-valine, as hydrochlorides on heating at 220 • C in the presence of PPA for 4 h to give the 2-substitutedBTs 29a and 29b in low yields (Scheme 14). However, 53.2% and 41.0% yields of the respective compounds were obtained when the corresponding amino acid ethyl esters was used [121]. Condensation of 5-amidino-substituted ATP with carboxylic acids by heating in the presence of PPA at 110-180 • C for 3 h as a method to prepare 6-amidino-2-aryl/heteroarylBTs 30a-u in 31-74% yields was also reported ( Figure 8) [122].

Other Acids as Catalysts
The use of PPA requires high temperatures (110-220 • C) and long reaction times (1-12 h). These harsh conditions depend on the starting materials' stability and are a limitant to generalizing this condensation. Therefore, as an alternative to PPA, other acids as catalysts have been designed to be used in this condensation.
2-SubstitutedBTs 31 were obtained from ATP and the corresponding carboxylic acid by treatment with P 2 O 5 /MeSO 3 H (1/10, w/w) while warming. The reaction was effective for a wide range of aliphatic and aromatic carboxylic acids. The general procedure involves treating a mixture of P 2 O 5 /MeSO 3 H (1/10, w/w) and o-ATP in the ratio 1.5 g/1.0 mmol with 1.0 equivalent of the corresponding carboxylic acid and warming for 10 h [123].
Yildiz et al. reported the condensation of ATP with several carboxylic acids in the presence of trimethylsilylpolyphosphate ester (PPSE) as the cyclodehydration reagent and on refluxing for 3-4 h (140 • C) to afford a series of 2-substitutedBTs 32 in 43-72% yields (Scheme 15). All 2-substitutedBTs were tested for their antibacterial activities against Grampositive and Gram-negative bacteria and antifungal activity against the fungus Candida albicans [124]. Jiang et al. used triphenylphosphine (Ph 3 P) as the catalyst in the condensation reaction of ATP with bromodifluoroacetic acid in the presence of 3 molar equivalents of carbon tetrabromide (CBr 4 ) in refluxing toluene for 24 h to prepare 2-bromodifluoromethylBT 34 in a 65% yield to be used as a building block in the subsequent reactions. The reaction mechanism involves the formation of imidoyl bromide and intramolecular ring-closure reaction, similar to the mechanism represented in Scheme 16 [126].
Sharghi et al., in a one-pot procedure, condensed ATP with several aliphatic or aromatic carboxylic acids using a MeSO 3 H/SiO 2 system as a dehydrating catalyst at and heating at 140 • C for 2-12 h to synthesize 2-substituted aliphatic and aromatic BTs 35 in 70-92% yields (Scheme 17). A simple work-up, using diverse carboxylic acids, and easy handling reaction conditions are the benefits of this method. The 2-(o-, m-, and p-NO 2 -phenyl)BTs were obtained in 35%, 11%, and 53% yields, respectively [127]. For instance, 2-chloromethylBT was obtained in a 92% yield on the condensation of ATP with chloroacetic acid and heating the product at 140 • C for 2.5 h, using MeSO 3 H/SiO 2 as the catalyst, in the synthesis of BT derivatives [128].
The cyclocondensation of ATP and aromatic carboxylic acids to give 2-substitutedBTs 36 in 60-87% yields has been carried out under mild conditions using tetrabutylammonium bromide (TBAB) as the reaction medium and triphenyl phosphite (TPP) as the catalyst (Scheme 18). Shorter reaction times, rapid isolation of products, and good yields are advantages of this method. The reaction was found to be general and quite tolerant to the nature of the substituted carboxylic acids. The mechanism shown in Scheme 19 is assumed to operate. Triphenyl phosphite reacts with aromatic carboxylic acids to produce the corresponding ester a, which reacts with o-aminothiophenol to form the phosphoester intermediate b. The thiol group of phosphoester b attacks the C=O to give, after intramolecular cyclization, the title products [129].  A series of 2-(3-butynoicamidophenyl)BTs 41 were synthesized starting from 4-fluoro-3-nitrobenzoic acid and ATP. Their antitumor activities against human tumor cell lines (HCT116, Mia-PaCa2, U87-MG, A549, NCI-H1975) were evaluated by an MTT assay [133].
2-SubstitutedBTs 42 were synthesized in 72-92% yields from the reaction of ATP with a set of substituted aromatic carboxylic acids using Samarium(III) triflate as a catalyst (Scheme 23). Short reaction times, aqueous reaction media, and easy work-up are the advantages of this method. The catalysts were reused without any appreciable loss of efficiency [134]. A simple trituration method for the synthesis of 2-substitutedBTs 43 from the reaction of N-protected amino acids and ATP using molecular iodine as a mild Lewis acid catalyst has been proposed (Scheme 24). The reaction occurs in one step that lasts for 20-25 min in solvent-free conditions to afford the products in 66-97% yields [135]. Scheme 24. Condensation of ATP with amino acids in presence of iodine.

Condensation on Direct Heating
In addition to the harsh conditions, such as toxic solvents, strong acidic conditions, high temperatures, and long reaction times, employed in condensation reactions of ATPs with carboxylic acids, the use of PPA as a catalyst and the side reactions carried out lead to the lowering of selectivities and low yields. Therefore, there is a strong demand for a highly efficient and environmentally benign method for the synthesis of these heterocycles. In this sense, the use of ionic liquids (ILs) as green solvents in organic synthesis has gained considerable importance due to their solvating ability, negligible vapor pressure, and easy recyclability. In addition, they have been shown to promote and catalyze organic transformations due to their high polarity. ILs can also be recovered and recycled many times with marginal loss.
Substituted 2-arylBTs 44 can be rapidly (10 min) synthesized in 80-94% yields by the condensation of a set of carboxylic acids with ATP under atmospheric conditions using the ionic liquid 1-butyl-3-methyl-imidazoliumtetraflouroborate ((bmim)BF 4 ) as a dissolvent and dehydrating agent at 100 • C (Scheme 25) [136]. Scheme 25. Condensation of ATP with p-substituted benzoic acids using the ionic liquid bnimBF 4 . In an autocatalytic procedure, ATP and trifluoroacetic acid (TFA) were heated to 70 • C for 16 h to produce the corresponding 2-(trifluoromethyl)BTs 45a (Scheme 26). Evaporation of the excess TFA afforded the product in a 99% yield. However, the same reaction with the electron-deficient 4-trifluoromethyl-substituted o-aminothiophenol produced the corresponding 2-trifluoromethylBT 45b in only 58% yield [137]. A metal-free methodology by the use of a base as an oxidant has been developed for the condensation of ATP with oxalic and malonic acids followed by a decarboxylation to afford BT 46a and 2-methylBT 46b in 80% and 82% yields, respectively (Scheme 27). Easy work-up procedure, high yield, and easy isolation of products are the advantages of this methodology [138].

Condensation with Esters
The condensation of esters with ATPs produces the corresponding thioester a (Scheme 4). The acyl group migrates to form the amide b (Scheme 4), which is cyclicized and then dehydrated with the aid of a Brönsted or Lewis acid to the corresponding 2-substitutedBTs, as depicted in Scheme 4.
Substituted ATPs have been condensed with methyl 4-amino-3-iodobenzoate ester under PPA on heating to 220 • C to produce 2-(4-aminophenyl)BT 47 in a 14% yield, instead of the expected iodinated compound (Scheme 28) [106]. In acid conditions, the iodo group is electrophylically substituted. The ATP amino group is cauterized and the nucleophile is blocked to directly form the corresponding amide and the thioester. Then the acyl group migration is carried out at a high temperature.  [139]. In this case, the neutralization regenerates the ATP amino group to form the corresponding amide for the cyclization to be continued. Phenolic esters were efficiently converted to 2-substitutedBTs 49 in a one-pot reaction by treatment with ATP in the presence of a catalytic amount of K 2 CO 3 and then converted to a thiolate salt on heating with N-methyl-2-pyrrolidone (NMP) at 100 • C (Scheme 30). The formation of a thioester b with the elimination of the corresponding phenol and migration of the acyl group to the nitrogen atom c can be proposed, followed by dehydration [79]. Polymer-bound esters were treated with ATP in the presence of AlMe 3 as the Lewis acid dehydrating agent in refluxing toluene to afford the 2-substitutedBts 50 as the cleavage products in a 46-75% yields (Scheme 31) [140]. 5-Fluoro ATP potassium salt was reacted with HCl, followed by the addition of (R)-4-methyl-oxazolidine-2,5-dione derived from d-alanine, to give the (1R)-1-(6-fluoro-1,3-BT-2-yl)ethanamine hydrochloride 52, which was transformed to its p-toluenesulfonate salt in an 81% yield (Scheme 35). This compound was used as the starting material in the synthesis of a series of diamides [143]. Scheme 35. Condensation of 5-fluoro ATP thiolate with (R)-4-methyl-oxazolidine-2,5-dione derived from d-alanine.

Condensation with Orthoesters
The general mechanistic pathway of condensation reactions of ATPs with orthoesters has been proposed as represented in Scheme 36. In an efficient procedure, 2-chloro-1,1,1-triethoxyethane was condensed with ATP in a versatile synthesis of 2-chloromethylBT 17 [145].
A series of 2-alkylBTs (R = H, Me, Et) 46a-c were synthesized in 81-86% yields from the reactions of ATP with orthoesters in the presence of catalytic amounts of Bi(III) salts, such as Bi(TFA) 3 , Bi(OTf) 3 , and BiOClO 4 xH 2 O, under solvent-free conditions at room temperature. High conversion, very short reaction times, cleaner reaction profiles, solventfree conditions, straightforward procedure, and use of low-toxic catalysts are the features of this protocol [146]. The same condensation was carried out in the presence of catalytic amounts of the eco-friendly and inexpensive ZrOCl 2 ·8H 2 O under solvent-free conditions to afford the compounds 46a-c in 93-97% yields. The reusability of the catalyst, high yields, very short reaction times (4-6 min), solvent-free reaction conditions, and an easy experimental and work-up procedure are the advantages of this protocol [147].
Silica-supported fluoroboric acid HBF 4 -SiO 2 was used as a catalyst in the condensation of ATP with orthoesters under solvent-free conditions at room temperature. A simple and environmentally benign synthesis of 2-aliphaticBTs 46a-e in 84-97% yields was carried out by this procedure in 45 min (Scheme 38) [148]. A solvent-free method, with sulfonated rice husk ash (RHA) as the solid acid catalyst, was developed for the condensation of ATP with orthoesters in the preparation of BT 46a and 2-methylBT 46b in 92% and 95% yields in 1 min. The catalyst could be reused five times without any loss of its catalytic activity (Scheme 42) [152]. Scheme 42. Sulfonated rice husk ash (RHA) as catalyst in the condensation of ATP with ortho esters.

Condensation with Acyl Chlorides
In this method, acid chlorides react with ATPs to produce directly the corresponding amides as intermediates. In general, tertiary amines are used to trap the chlorohydric acid produced in the reaction. After the cyclization, the generated ammonium chloride salt formed is used as a catalyst in the dehydration of the 2-hydroxy thiazolidine intermediate to produce 2-substitutedBTs. Sometimes, any base is used. In this case, hydrochloric acid is used as the dehydrating agent.
Via a general method, ATP with 1-methyl-pyrrolidinone as the solvent was condensed with a stoichiometric amount of the corresponding acid chloride, added slowly at room temperature under an inert atmosphere. The corresponding 2-arylBTs 55 were obtained in 82-95% yields (Scheme 43). The reaction mixture was heated at 100 • C for 1 h. The intermediate di-irido and the six-coordinated mononuclear iridium (III) dopants of the above ligands were synthesized and characterized [153,154]. 4-Methyl-ATP was condensed with chloroacetyl chloride in the presence of Et 3 N and EtOAc as the solvent on stirring from 0 • C to room temperature to produce in situ the corresponding 5-methyl-2-chloromethylBT 56, which was treated with thiourea to afford the more stable isothiouronium salt (Scheme 44) [155]. BTyl compounds 59a and 59b, synthesized from the corresponding dialdehydes 57a,b and 4-amino-3-mercaptobenzonitrile, were converted to the corresponding chlorocarbonyl derivatives 61a and 61b, which were condensed with 4-amino-3-mercaptobenzonitrile by Route A to produce the biscyanoBTyl compounds 61a and 61b in about 75% yields (Scheme 45). By Route B, 5-(4-carboxyphenyl)-2-furylcarboxylic acid 58a and 5-(4carboxyphenyl)-2-thienylcarboxylic acid 58b were converted to the dichlorocarbonyl derivatives 60a and 60b and then were condensed with 4-amino-3-mercaptobenzonitrile to afford 62a and 62b in about 35% yields (Scheme 45). Route B has one step less than Route A. However, the overall yield of the reactions was considerably lower [156].

Scheme 45. Two condensation ways to produce biscyanoBTyl compounds.
A regioselective one-pot synthesis of 2-arylBTs 63 was achieved in excellent isolated yields by the condensation of ATP and substituted benzoyl chlorides under ambient conditions using the ionic liquid mixtures 1-butylimidazolium tetraflouroborate ([Hbim]BF 4 ) and 1,3-di-n-butylimidazolium tetrafluoroborate ([bbim]BF 4 ) as the reaction medium and the reaction promoter, respectively (Scheme 46). The absence of a catalyst, room temperature conditions, and non-volatile ILs makes this protocol green and environment friendly [157]. Chen et al. condensed ATP with isophthaloyl or terephthaloyl fluorides attached to a polyethylene glycol methyl ether PEG resin in a liquid-phase synthesis of two 2-aromaticBTs 64 (Scheme 47). The cleavage from PEG was achieved by treatment with sodium methoxide in methanol for 12 h. The compounds 64 were obtained in four steps, with poor isolated yields (22% and 37%) [159].
The synthesis of S-alkyl/arylBT-2-carbothioates 77 through a three-component reaction was reported from the condensation of substituted ATPs with thiols/oxalyl chloride system using 10 mol % of tetrabutylammonium iodide (TBAI) as the catalyst in acetonitrile as a solvent (Scheme 55). BTs and thioesters were formed via simultaneous C-N and C-S bond formation in 56-80% yields with several substrates. The synthesized derivatives were tested for their antimicrobial activity against the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL) [166]. To understand the reaction mechanism, treatment of ATP with oxalyl chloride was carried out in the same conditions; however, the corresponding bis-BT 78 was obtained in only a 25% yield (Scheme 56). A useful protocol for the preparation of substituted 2-aminoBTs 78 was presented. Substituted ATPs were reacted with thiocarbamoyl chlorides under the catalysis of copper in a tandem manner to produce compounds 78 with 70-91% yields (Scheme 58). The broad substrate scope, a short reaction time, mild reaction conditions, easy performance, and excellent yields make this protocol attractive for the preparation of some biologically active compounds [167]. Various carboxylic acid chlorides were reacted with ATP in the presence of KF/Al 2 O 3 (25% mol) as a heterogeneous base catalyst in refluxing dry acetonitrile at room temperature to form the corresponding 2-substitutedBTs 79 in 87-97% yields, with good recyclability of the catalyst (Scheme 59). However, the condensation of o-ATP with the mixture of acetic and benzoic anhydrides as carboxylic acid derivatives produced the BTs in 90% and 91% yields [168].

Condensation with Nitriles
A proposed mechanism for this reaction is via the formation of an amidine a as an intermediate and subsequent cyclization followed by a deamination to afford the 2-substitutedBT (Scheme 60). This reaction can be catalyzed to accelerate the reaction. A convenient and efficient method for the synthesis of 2-substitutedBTs 85 in 50-95% yields was carried out from the condensation of substituted ATPs with substituted benzonitriles by the use of trifluoromethanesulfonic acid on heating at 100 • C for 12 h (Figure 10). The Bronsted-acid-catalyzed cyclization reaction was performed under metal-and solventfree conditions [173].

Condensation with Amides
In this case, deamination occurs to form the corresponding amide. Then, cyclization and dehydration produce 2-substitutedBTs. In some cases, this reaction requires to be catalyzed.
3-(BT-2-yl)coumarins 86 were prepared in 61-70% yields from the condensation of ATP with the corresponding 2-iminocoumarin-3-carboxamide in reflux with the minimum amount of n-butanol until the evolution of ammonia stops (1-1.5 h) (Scheme 66) [174]. The synthesis of several substituted BTs 87 in 50-94% yields was carried out from the condensation of substituted ATPs with 2-acylpyridazin-3(2H)-ones as acyl transfer agents under transition-metal-free and eco-friendly conditions. The reaction was efficient, green, and economical, with several applications in organic synthesis and in medicinal and industrial chemistry (Scheme 67) [175]. In an efficient and mild protocol, several substituted ATPs were condensed with thioamides to produce 2-substitutedBTs 89 in 62-93% yields using CBr 4 as the catalyst under solvent-and metal-free conditions (Scheme 69). This condensation process involves the activation of a thioamide through halogen bond formation between the sulfur atom of the thioamide and the bromine atom of the CBr 4 molecule. The presence of halogen-bonding interaction between N-methylthioamides and tetrabromomethane was demonstrated. Substituted 2-alkyl-and 2-arylBTs could be obtained from this methodology [177].
A simple, economical, and metal-free approach for the synthesis of 2-substitutedBTs 90 was reported in 60-87% yields from the condensation of substituted ATP and DMF derivatives, using imidazolium chloride (50% mmol) as the only promoter, without any other additive (Scheme 70) [178]. The proposed mechanistic pathway is as described in Scheme 71.

Condensation under Microwave Irradiation (MWI)
The Montmorillonite KSF Clay minerals act as strong Bronsted acids and have been used as solid, non-corrosive catalysts in the condensation of two orthoesters with ATP under toluene reflux or a solvent-free condition under MWI to produce BT and 2-methylBT 46 in 69% and 74% yields, respectively (Scheme 72) [179]. To improve yields, a MWI-assisted procedure to condense ATP with 2-chloroacetyl chloride in acetic acid to produce 2-chloromethylBT 17 was carried out for a 90% yield in 10 min [182].
Several aliphatic and aromatic carboxylic acids were condensed with ATP in the presence of 0.35 equivalents of Lawesson's reagent as promoters under solvent-free MWI (300 W, 190 • C) for 0.5-4 min to afford 2-substitutedBTs 93 with good yields (Scheme 75). In this methodology, Lawesson's reagent in situ converts carboxylic acids to thiocarboxylic acids, which are cyclocondensed with desulfhydration. The same protocol was used directly with thiobenzoic acid to afford 2-phenylBT in quantitative yields in 1 min [183]. Gupta et al. condensed ATP with various benzoic acid derivatives employing a catalytic quantity of molecular iodine (I 2 ) as the dehydrating agent in a one-pot, solidphase, solvent free, and MWI-assisted reaction to obtain 2-arylBTs 94 in 10 min with 60-70% yields (Scheme 76) [184]. Less time consumption and lower cost compared with the use of PPA and 1-pentyl-3-methyl imidizolium bromide [pmim]Br catalyst are the benefits of this procedure.
Panda et al. discovered that an excess of ATP (10 equiv.) and benzoyl benzotriazolide (1 equiv.) was coupled under microwave heating at 70 • C for 1 h in 91-95% yields without any catalyst or solvent used to produce 2-substituteBTs 99 (Scheme 81). The liquid o-aminothiophenol acts as both a solvent and a reagent. The same reaction under conventional heating was less efficient [191]. Condensation of ATP with (un)substituted p-aminobenzoic acids under the action of melamine formaldehyde resin (MFR)-supported sulfuric acid under microwave irradiation (900 W) and solvent-free conditions was performed (Scheme 83). The simple method afforded 2-(4-aminophenyl)BTs 101 in 81-88% yields in 6-8 min. The catalyst could be recycled three times, with the yield lowering from 87% to 80% [192]. A metal-free and catalytic method for the synthesis of 2-substitutedBTs 102 and 103 in 815-92% yields was carried out involving the condensation of ATP with N-protected amino acids and carboxylic acids under MW irradiation (Scheme 84). The reactions proceeded through a two-step mechanism. The coupling step was carried out with ethyl 2-cyano-2-(2nitrobenzenesulfonyloxyimino)acetate (I) (ortho-No-sylOXY), and the cyclization step took place with the use of para-toluenesulfonic acid as the catalyst [193]. Luo et al. found that 2-chloromethylBT 17 could be obtained in an 87% yield from the condensation of ATP with chloroacetyl chloride in acetic acid under MW irradiation for 10 min. The MW-assisted procedures were efficient and environmentally friendly, and used less time, compared with traditional methods [194].
A method for the synthesis of a series of 2-substitutedBTs 104 in 82-92% yields was developed involving the condensation of ATP with a series of carboxylic acids using Amberlyst-15 as a recyclable catalyst under ultrasound irradiation in water (Scheme 85). This methodology does not use hazardous organic solvents and is carried out in an inert or anhydrous atmosphere [195].

Condensation of o-Aminothiophenol Disulfides (ATPDs)
In this condensation reaction, a reducing agent was required before or after the amide formation to afford the corresponding amidethiophenoles, which were cyclized to the 2-substitutedBTs.
Shi et al., in short reaction times, synthesized 2-arylBTs 107 in 70-92% yields via the reductive cyclization of bis-(2-benzalaminophenyl)disulfide promoted by a titanium tetrachloride (TiCl 4 )/Samarium (Sm) system using tetrahydrofuran (THF) as a solvent (Scheme 87) [197]. 2-ArylBTs 108 were synthesized using a PCl 3 and DBU as the organic base to promote the cleavage/acylation/cyclization tandem reaction of the disulfides of ATP and aromatic carboxylic acids. PCl 3 acted as both acylating and disulfide cleaving reagents, which prompted the disulfides of ATP to react with the aromatic carboxylic acid (Scheme 88) [198].  This method was used to prepare the amyloid probe 2-(4-aminophenyl)-6-methoxyBT. A plausible mechanism was proposed as depicted in Scheme 90. A nucleophilic attack of tributylphosphine promotes the cleavage of the S-S bond of disulfide to produce a thiolate phosphonium salt a. Thiolate deprotonates the carboxylic acid, and the generated carboxylate reacts with the phosphonium salt to form a pentacoordinate acyloxyphosphonium intermediate b. Intramolecular nucleophilic attack of the amino group on the carbonyl produces amide c and tributylphosphoxide. Finally, a nucleophilic attack of the thiol group on the carbonyl of the amide c followed by dehydration to leads to the BT.

Condensation by Cyclization of CO 2 as the Raw Material
In this reaction, the CO 2 must be activated to form a formiate ester or formamide as an intermediate to be condensed with ATPs to produce the corresponding BTs.
A series of substituted o-ATPs were cyclized with CO 2 in the presence of diethylsilane and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) as the catalyst at 5 MPa to synthesize substituted BTs 110 in 35-82% yields (Scheme 91) [200]. The proposed mechanism shows that hydrosilane played an important role in activating CO 2 in the formation of compounds 110. Scheme 91. CO 2 activated with Et 2 SiH in the condensation of substituted ATPs.
The same authors cyclized substituted ATPs with CO 2 and hydrosilane to produce a series of substituted BTs 111a-j in up to 99% yields under metal-free and mild conditions using the acetate-based ionic liquid ([Bmim][OAc]) as a catalyst at 60 • C and 0.5 Mpa (Scheme 92) [201]. The IL was reused five times without change. A possible mechanism was proposed as shown in Scheme 88. The same series of BTs 111a-j were obtained in 42-99% yields by an effective cyclization of substituted ATPs with DMF in the presence of B(C 6 F 5 ) 3 combined with atmospheric CO 2 (Scheme 93). The outgoing intermediate dimethylamine in b further reacted with CO 2 and silane catalyzed by B(C 6 F 5 ) 3 , forming trimethylamine, which drove the cyclization reaction to the right, promoting the reaction [202].
A scalable CO 2 -mediated synthesis of BT 111a in 86% yields was developed. ATP was cyclized with DMF as the carbon source in water as the solvent in the presence of CO 2 . The CO 2 used could be recycled (Scheme 94) [203].
Chun et al. reported the synthesis of an extended series of substituted BTs 112a-n in 33-84% yields from substituted ATPs and CO 2 using poly(3,4-dimethyl-5-vinylthiazolium) iodide as a precatalyst, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) as a base, and phenylsilane as the reductant to in situ generate N-heterocyclic carbenes a (NHCs) by deprotonation (Scheme 95), which capture CO 2 to be transferred to phenylsilane as the formiate group in intermediate c. Then o-ATP forms the formyltioester d. The reaction was successfully carried out under mild conditions (1 atm of CO 2 and 60-70 • C), with a broad substrate scope and functional group tolerance. The precatalyst salt was recovered and reused several times without any loss of activity [204].

Conclusions
Investigation into the synthesis of BT derivatives has increased in recent years. For example, in the past 5 years, we found 19 article reviews related to the strategies of synthesis and biological activities of BTs, of which 8 were reported in 2020. It shows the importance of the BT core in the pharmaceutical chemistry field. These works included only a few methods on the condensation of ATPs with carboxylic acids and their derivatives. Accordingly, in our article review, we have reported an investigation of about 20 years on the aspects of the research progress related to the condensation of ATPs with carboxylic acids and their derivatives, such as acid chlorides, amides, esters, orthoesters, nitriles, and thioesters, including carbon dioxide (CO 2 ), as starting materials.
In this review, we found that the condensation of ATPs with carboxylic acids in the presence of PPA as the catalyst is still popular, although high temperatures, from 110 to 220 • C, and reaction times from 0.5 to 18 h are required. The best yields, of 80% to 90%, were obtained on heating at 140 • C for 24 h. These condensations have been carried out using other catalyst, such as P 2 O 5 /MeSO 3 H, PPA/H 3 PO 4 , trimethylsilylpolyphosphate ester (PPSE), MeSO 3 H/SiO 2 , triphenylphosphine (Ph 3 P), triphenyl phosphite (TPP), Samarium(III) triflate, trifluoroacetic acid (TFA), and iodo (I 2 ). In these cases, the yields were from 60% to 99% but less reaction times were required. Few examples were found in which 80% to 90% yields resulted on heating in ionic liquids (10 min), on direct heating (16 h), as well as on refluxing in high-boiling-point solvents (8 h).
The condensation of ATPs with esters on heating under acid catalysts such as PPA, K 2 CO 3 /NMP, and AlMe 3 ; under stirring; under direct heating; or in refluxing solvents depending on the ester has been carried out leading to low (14%) to high (92%) yields.
Acid chlorides and a nitrile-substituted ATP were condensed in refluxing chlorobenzene for 70 h under a stream of nitrogen to give the product in a 35% yield. The same condensation with unsubstituted ATP in refluxing chlorobenzene for 3 h gives the condensation products in 73-79% yields. On stirring in toluene for 15 min or 1 h at room temperature, the condensation yields were 50-98%. On refluxing in acetic acid, the yields increased to 70-88%. However, using n-methyl-pyrrolidone as a solvent on heating at 100 • C for 1 h gave the best results (82-95%). Ionic liquids such as 1-butylimidazolium tetrafluoroborate ([Hbim]BF 4 ) and 1,3-di-n-butylimidazolium tetra-fluoroborate ([bbim]BF 4 ) as reaction media were used with excellent isolated yields. Pyridine as a base to trap the liberated HCl in the presence of o-benzene-di-sulfonamide as a catalyst has been used to produce BTs in 42-87% yields. On heating for 12 h at 100 • C with NaHSO 4 -SiO 2 as a catalyst under solvent-free conditions, the condensation yields were 86-89%. The CuCl 2 /K 2 CO 3 and KF/Al 2 O 3 systems were excellent heterogeneous catalysts on refluxing in an adequate solvent to give 70% to 97% yields in this condensation. Acid fluorides attached to PEG resins were used, but poor isolated yields were obtained in the condensation (22-37%).
Condensation with nitriles produced moderate yields on direct heating with solvents or with the use of catalysts such as PPA. On using a heterogeneous catalyst such as Cu(OAc) 2 on refluxing in ethanol or trifluoromethanesulfonic acid, BTs in best yields (50-97%) were produced.
Amides were condensed with ATPs on refluxing in solvents such as butanol or toluene by short reaction times (20 min-3 h) to obtain 50% to 94% yields. The use of imidazolium chloride or tetrabromo-methane as catalysts produced BTs in 60-90% yields, but 8-24 h were required. Condensation with substituted formamides in the presence of Zn(OAc) 2 ·H 2 O as a catalyst gives BTs in up to 95% yield.
Condensation reactions using microwave irradiation is the green method of choice because this method reduces the reaction time (less than 1 h), with or without the use of solvents, with good to excellent yields (50-97%).
Only one example on the use of ultrasound irradiation in the condensation of aromatic and aliphatic carboxylic acids was found with very good yields (82-92%).

Conflicts of Interest:
The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.