Synthetic Approaches to Biologically Active C-2-Substituted Benzothiazoles

Numerous benzothiazole derivatives are used in organic synthesis, in various industrial and consumer products, and in drugs, with a wide spectrum of biological activity. As the properties of the benzothiazole moiety are strongly affected by the nature and position of substitutions, in this review, covering the literature from 2016, we focus on C-2-substituted benzothiazoles, including the methods of their synthesis, structural modification, reaction mechanisms, and possible pharmacological activity. The synthetic approaches to these heterocycles include both traditional multistep reactions and one-pot atom economy processes using green chemistry principles and easily available reagents. Special attention is paid to the methods of the thiazole ring closure and chemical modification by the introduction of pharmacophore groups.


Intramolecular Formation of the C-2-Substituted Benzothiazole Ring
Benzothiazoles 1a-y with alkyl, aryl and hetaryl substituents in position 2 of the rin were prepared in moderate to good yields by a metal-free atom-economic procedure [107 The cascade process and the R3 group transfer were initiated by di(t-butyl)peroxid (DTBP) in fluorobenzene. The reaction started with the homolytic fission of DTBP upo heating to give t-butoxy radical, which suffered β-scission to give methyl radical. The pro posed mechanism is presented in Scheme 1. Scheme 1. DTBP-promoted formation of benzothiazoles 1a-y from ortho-isocyanoaryl thioethers.
The copper NHC complex-catalyzed intramolecular S-arylation of various 2 halogenothioanilides was investigated as a route to 2-arylbenzothiazoles 2a-f [108 (Scheme 2). Good yields were obtained both for electron donor and electron acceptor sub stituents in the aryl rings. The mechanism, including two-electron Cu(I)/Cu(III) catalyti cycles with the intramolecular cyclization of 2-halogenothioanilides to 2-arylbenzothia zoles, was proposed.
A series of new "head-to-head" aniline-based derivatives of bis-benzothiazole were obtained and their antiproliferative activity was assessed [14]. In the presence of Br2, benzidine reacts with potassium thiocyanate via cyclization to bis(benzothiazole)diamine. Its hydrolysis with KOH leads to the key intermediate, 3,3'-bis(mercapto)benzidine. The latter reacts with p-substituted benzaldehydes to give bis-substituted benzothiazoles 13a-j (Scheme 10). The products with electron-donor substituents in the benzene ring are less toxic and more effective. DMSO acts both as the solvent and the oxidant in the metal-free ecologically safe synthesis of C-2-substituted benzothiazoles 14a-g and naphtho [2,1-d]thiazoles 15a-z Scheme 9. Benzothiazoles 12a-c from aniline and sulfinylbis(2,4-dihydroxyphenyl) methanethione.
A series of new "head-to-head" aniline-based derivatives of bis-benzothiazole were obtained and their antiproliferative activity was assessed [14]. In the presence of Br 2 , benzidine reacts with potassium thiocyanate via cyclization to bis(benzothiazole)diamine. Its hydrolysis with KOH leads to the key intermediate, 3,3'-bis(mercapto)benzidine. The latter reacts with p-substituted benzaldehydes to give bis-substituted benzothiazoles 13a-j (Scheme 10). The products with electron-donor substituents in the benzene ring are less toxic and more effective. Scheme 8. Synthesis of fluorinated benzothiazole rhodacyanines 11a-q with antileishmanial activity.
A series of new "head-to-head" aniline-based derivatives of bis-benzothiazole were obtained and their antiproliferative activity was assessed [14]. In the presence of Br2, benzidine reacts with potassium thiocyanate via cyclization to bis(benzothiazole)diamine. Its hydrolysis with KOH leads to the key intermediate, 3,3'-bis(mercapto)benzidine. The latter reacts with p-substituted benzaldehydes to give bis-substituted benzothiazoles 13a-j (Scheme 10). The products with electron-donor substituents in the benzene ring are less toxic and more effective. DMSO acts both as the solvent and the oxidant in the metal-free ecologically safe synthesis of C-2-substituted benzothiazoles 14a-g and naphtho [2,1-d]thiazoles 15a-z Scheme 10. Synthesis of symmetrical bis-benzothiazoles 13a-j from benzidine. DMSO acts both as the solvent and the oxidant in the metal-free ecologically safe synthesis of C-2-substituted benzothiazoles 14a-g and naphtho [2,1-d]thiazoles 15a-z from N-substituted arylamines and elemental sulfur (Scheme 11) [111]. The advantages of the method are the use of easily accessible anilines, a variety of 1 and 2-naphthylamines and 2-anthranylamine, and tolerance to a wide range of functional groups. 1,3 and 1,4bisnaphtho [2,1-d]thiazoles linked by the benzene bridge have also been synthesized. The electron-donating groups in the aniline fragment notably increase the yield of the target products. The proposed mechanism is shown in Scheme 11, using the example of naphthylamine. First, amine is oxidized by DMSO to imine (A). The electrophilic attack of elemental sulfur S n to the ortho-position of imine (A) gives intermediate (B). The elimination of sulfur S n-1 and the proton results in the imine thiolate (C), which undergoes nucleophilic intramolecular cyclization to thiazoline (D). Finally, oxidative aromatization of the latter gives rise to the target annelated products 15. electron-donating groups in the aniline fragment notably increase the yield of the target products. The proposed mechanism is shown in Scheme 11, using the example of naphthylamine. First, amine is oxidized by DMSO to imine (A). The electrophilic attack of elemental sulfur Sn to the ortho-position of imine (A) gives intermediate (B). The elimination of sulfur Sn-1 and the proton results in the imine thiolate (C), which undergoes nucleophilic intramolecular cyclization to thiazoline (D). Finally, oxidative aromatization of the latter gives rise to the target annelated products 15. Scheme 11. Metal-free synthesis of benzothiazoles 14a-g and 15a-z from N-substituted arylamines and elemental sulfur.
Most reactions of intermolecular formation of the C-2-substituted benzothiazole ring are based on the use of readily accessible 2-aminothiophenols and green chemistry principles. An example is the reaction of direct oxidative condensation of aminothiophenols and aliphatic, heterocyclic or aromatic alcohols to benzothiazoles 16a-m with different substituents upon irradiation with visible light in the presence of a photocatalyst (Scheme 12) [91]. The process is scalable and economic; the yield of the products depends on the electronic and steric effects of the alcohol molecule. The reaction mechanism includes the oxidation of alcohols to aldehydes, the condensation of the latter with ortho-aminophenols to imine/benzothiazolines, and their oxidation to 2-substituted benzothiazoles. Scheme 12. Photocatalytic synthesis of benzothiazoles 16a-o from о-aminothiophenols and alcohols. Scheme 11. Metal-free synthesis of benzothiazoles 14a-g and 15a-z from N-substituted arylamines and elemental sulfur.
Most reactions of intermolecular formation of the C-2-substituted benzothiazole ring are based on the use of readily accessible 2-aminothiophenols and green chemistry principles. An example is the reaction of direct oxidative condensation of aminothiophenols and aliphatic, heterocyclic or aromatic alcohols to benzothiazoles 16a-m with different substituents upon irradiation with visible light in the presence of a photocatalyst (Scheme 12) [91]. The process is scalable and economic; the yield of the products depends on the electronic and steric effects of the alcohol molecule. The reaction mechanism includes the oxidation of alcohols to aldehydes, the condensation of the latter with ortho-aminophenols to imine/benzothiazolines, and their oxidation to 2-substituted benzothiazoles.
bisnaphtho [2,1-d]thiazoles linked by the benzene bridge have also been synthesized. The electron-donating groups in the aniline fragment notably increase the yield of the target products. The proposed mechanism is shown in Scheme 11, using the example of naphthylamine. First, amine is oxidized by DMSO to imine (A). The electrophilic attack of elemental sulfur Sn to the ortho-position of imine (A) gives intermediate (B). The elimination of sulfur Sn-1 and the proton results in the imine thiolate (C), which undergoes nucleophilic intramolecular cyclization to thiazoline (D). Finally, oxidative aromatization of the latter gives rise to the target annelated products 15. Scheme 11. Metal-free synthesis of benzothiazoles 14a-g and 15a-z from N-substituted arylamines and elemental sulfur.
Most reactions of intermolecular formation of the C-2-substituted benzothiazole ring are based on the use of readily accessible 2-aminothiophenols and green chemistry principles. An example is the reaction of direct oxidative condensation of aminothiophenols and aliphatic, heterocyclic or aromatic alcohols to benzothiazoles 16a-m with different substituents upon irradiation with visible light in the presence of a photocatalyst (Scheme 12) [91]. The process is scalable and economic; the yield of the products depends on the electronic and steric effects of the alcohol molecule. The reaction mechanism includes the oxidation of alcohols to aldehydes, the condensation of the latter with ortho-aminophenols to imine/benzothiazolines, and their oxidation to 2-substituted benzothiazoles. Another example is the green synthesis of benzothiazoles 17a-t by the condensation of 2-aminothiophenol with various aldehydes in the presence of heterogeneous catalysts. As such, SnP 2 O 7 prepared from monoammonium phosphate and SnCl 2 solution, or Sm(NO 3 ) 3 ·6H 2 O applied on nanosized silica gel, were used. As solvents, ethanol or methanol were employed [85] (Scheme 13, upper reaction). The catalysts can be recycled five times without notable loss of the catalytic activity. Benzaldehydes with electron acceptor or electron donor groups, as well as heterocyclic aldehydes, readily entered the reaction with 2-aminothiophenol (yields: 85-96%); lower yields (68-73%) were obtained for aliphatic aldehydes. However, with microwave assistance, the yield of the reaction of 2-aminothiophenol with aliphatic aldehydes may reach 98%. The reaction was carried out without solvent in the presence of charcoal and silica gel (Scheme 13, bottom reaction) [50]. Microwave assistance in the presence of catalytic amounts of Amberlite IR-120 resin also allowed the authors to obtain a large series of aryl-and hetarylbenzothiazoles 18a-g containing different functional groups from aldehydes and 2-aminothiophenol [24].
or electron donor groups, as well as heterocyclic aldehydes, readily entered the with 2-aminothiophenol (yields: 85-96%); lower yields (68-73%) were obtained phatic aldehydes. However, with microwave assistance, the yield of the reaction o nothiophenol with aliphatic aldehydes may reach 98%. The reaction was carried o out solvent in the presence of charcoal and silica gel (Scheme 13, bottom reacti Microwave assistance in the presence of catalytic amounts of Amberlite IR-120 r allowed the authors to obtain a large series of aryl-and hetarylbenzothiazoles 18 taining different functional groups from aldehydes and 2-aminothiophenol [24]. Scheme 13. Synthesis of benzothiazoles 17a-t and 18a-g from 2-aminothiophenol and alde the use of heterogeneous catalysts or with microwave assistance. In other ecologically friendly syntheses of C-2-substituted benzothiazoles fr nothiophenols, cheap water-soluble urea nitrate [35], ionic liquid with the sulfona group playing the role of the heterogeneous catalyst and the solvent (BAIL GEL) a biocatalyst in the form of a natural carrier of calcined limpet shells coated wi were used [112].
A simple and efficient synthesis of 2-alkylbenzothiazoles 19a-g was perform two-step reaction including the condensation of 2-aminothiophenol with alipha hydes in the presence of molecular sieves 4Å followed by the oxidation of the fo alkyl-2,3-dihydrobenzo[d]thiazoles with pyridinium chlorochromate (PCC) on s (Scheme 14) [84]. Distinct from aldehydes, ketones react with 2-aminothiophenol via their activ ylene group, as proven by the carbonyl group remaining intact in the products. series of aromatic 2-acylbenzothiazoles 20a-k was obtained from 2-aminothioph addition to aromatic or heteroaromatic ketones by reflux in ethanol with CuBr2 a idant (Scheme 15) [101]. Apparently, the reaction proceeds with N-nucleophilic s tion in α-bromoketone generated from the ketone and CuBr2. The formed α-amin Scheme 13. Synthesis of benzothiazoles 17a-t and 18a-g from 2-aminothiophenol and aldehydes by the use of heterogeneous catalysts or with microwave assistance.
In other ecologically friendly syntheses of C-2-substituted benzothiazoles from aminothiophenols, cheap water-soluble urea nitrate [35], ionic liquid with the sulfonate anion group playing the role of the heterogeneous catalyst and the solvent (BAIL GEL) [100], or a biocatalyst in the form of a natural carrier of calcined limpet shells coated with ZnCl 2 were used [112].
A simple and efficient synthesis of 2-alkylbenzothiazoles 19a-g was performed by a two-step reaction including the condensation of 2-aminothiophenol with aliphatic aldehydes in the presence of molecular sieves 4Å followed by the oxidation of the formed 2-alkyl-2,3-dihydrobenzo[d]thiazoles with pyridinium chlorochromate (PCC) on silica gel (Scheme 14) [84].
As such, SnP2O7 prepared from monoammonium phosphate and SnCl2 solution, or Sm(NO3)3·6H2O applied on nanosized silica gel, were used. As solvents, ethanol or methanol were employed [85] (Scheme 13, upper reaction). The catalysts can be recycled five times without notable loss of the catalytic activity. Benzaldehydes with electron acceptor or electron donor groups, as well as heterocyclic aldehydes, readily entered the reaction with 2-aminothiophenol (yields: 85-96%); lower yields (68-73%) were obtained for aliphatic aldehydes. However, with microwave assistance, the yield of the reaction of 2-aminothiophenol with aliphatic aldehydes may reach 98%. The reaction was carried out without solvent in the presence of charcoal and silica gel (Scheme 13, bottom reaction) [50]. Microwave assistance in the presence of catalytic amounts of Amberlite IR-120 resin also allowed the authors to obtain a large series of aryl-and hetarylbenzothiazoles 18a-g containing different functional groups from aldehydes and 2-aminothiophenol [24]. Scheme 13. Synthesis of benzothiazoles 17a-t and 18a-g from 2-aminothiophenol and aldehydes by the use of heterogeneous catalysts or with microwave assistance.
In other ecologically friendly syntheses of C-2-substituted benzothiazoles from aminothiophenols, cheap water-soluble urea nitrate [35], ionic liquid with the sulfonate anion group playing the role of the heterogeneous catalyst and the solvent (BAIL GEL) [100], or a biocatalyst in the form of a natural carrier of calcined limpet shells coated with ZnCl2 were used [112].
A simple and efficient synthesis of 2-alkylbenzothiazoles 19a-g was performed by a two-step reaction including the condensation of 2-aminothiophenol with aliphatic aldehydes in the presence of molecular sieves 4Å followed by the oxidation of the formed 2alkyl-2,3-dihydrobenzo[d]thiazoles with pyridinium chlorochromate (PCC) on silica gel (Scheme 14) [84]. Distinct from aldehydes, ketones react with 2-aminothiophenol via their active methylene group, as proven by the carbonyl group remaining intact in the products. Thus, a series of aromatic 2-acylbenzothiazoles 20a-k was obtained from 2-aminothiophenol, in addition to aromatic or heteroaromatic ketones by reflux in ethanol with CuBr2 as the oxidant (Scheme 15) [101]. Apparently, the reaction proceeds with N-nucleophilic substitution in α-bromoketone generated from the ketone and CuBr2. The formed α-aminoketone Scheme 14. Synthesis of benzothiazoles 19a-g from 2-aminothiophenol and aliphatic aldehydes in the presence of molecular sieves.
Distinct from aldehydes, ketones react with 2-aminothiophenol via their active methylene group, as proven by the carbonyl group remaining intact in the products. Thus, a series of aromatic 2-acylbenzothiazoles 20a-k was obtained from 2-aminothiophenol, in addition to aromatic or heteroaromatic ketones by reflux in ethanol with CuBr 2 as the oxidant (Scheme 15) [101]. Apparently, the reaction proceeds with N-nucleophilic substitution in α-bromoketone generated from the ketone and CuBr 2 . The formed α-aminoketone is further brominated by CuBr 2 and cyclized by the nucleophilic attack of the thiol group on the α-carbon atom with the elimination of HBr and the closing of the ring, as shown in Scheme 15. In the final step, dehydrogenation with a reduction of CuBr 2 to CuBr gives the target 2-acylbenzothiazoles 20a-k.
is further brominated by CuBr2 and cyclized by the nucleophilic attack of the thiol group on the α-carbon atom with the elimination of HBr and the closing of the ring, as shown in Scheme 15. In the final step, dehydrogenation with a reduction of CuBr2 to CuBr gives the target 2-acylbenzothiazoles 20a-k. Scheme 15. The synthesis and possible mechanism of formation of 2-acylbenzothiazoles 20a-k from 2-aminothiophenol and ketones in ethanol.
For the synthesis of new benzothiazole-based hemicyanine sensitizers for solar cells, the ring closure was performed by the reaction of 2-aminothiophenol with isopropyl methyl ketone in the presence of acetic anhydride. Then, 2-methylbenzothiazole formed in a practically quantitative yield reacted with 1,2-oxathiane 2,2-dioxide to give the corresponding sulfonates and, finally, by the reaction with dimethylaminobenzaldehyde or 3,4dihydroxycyclobut-3-ene-1,2-dione, new sensitizers 21 and 22 were formed (Scheme 16) [56,57]. Several groups have developed the synthesis of C-2-substituted benzothiazoles 23ac from 2-aminothiophenols and β-diketones by the use of effective, recycled, cheap and ecologically safe catalysts, such as the montmorillonite clay KSF [113], long-chain ionic liquids [114], sodium dichloroiodate [115], or the Zr-based organometallic catalyst MOF-808 [116]. The mechanism given in Scheme 17 is an example of condensation with the participation of montmorillonite clay [113]. The reaction includes keto-enol For the synthesis of new benzothiazole-based hemicyanine sensitizers for solar cells, the ring closure was performed by the reaction of 2-aminothiophenol with isopropyl methyl ketone in the presence of acetic anhydride. Then, 2-methylbenzothiazole formed in a practically quantitative yield reacted with 1,2-oxathiane 2,2-dioxide to give the corresponding sulfonates and, finally, by the reaction with dimethylaminobenzaldehyde or 3,4-dihydroxycyclobut-3-ene-1,2-dione, new sensitizers 21 and 22 were formed (Scheme 16) [56,57].
is further brominated by CuBr2 and cyclized by the nucleophilic attack of the thiol group on the α-carbon atom with the elimination of HBr and the closing of the ring, as shown in Scheme 15. In the final step, dehydrogenation with a reduction of CuBr2 to CuBr gives the target 2-acylbenzothiazoles 20a-k. Scheme 15. The synthesis and possible mechanism of formation of 2-acylbenzothiazoles 20a-k from 2-aminothiophenol and ketones in ethanol.
For the synthesis of new benzothiazole-based hemicyanine sensitizers for solar cells, the ring closure was performed by the reaction of 2-aminothiophenol with isopropyl methyl ketone in the presence of acetic anhydride. Then, 2-methylbenzothiazole formed in a practically quantitative yield reacted with 1,2-oxathiane 2,2-dioxide to give the corresponding sulfonates and, finally, by the reaction with dimethylaminobenzaldehyde or 3,4dihydroxycyclobut-3-ene-1,2-dione, new sensitizers 21 and 22 were formed (Scheme 16) [56,57]. Several groups have developed the synthesis of C-2-substituted benzothiazoles 23ac from 2-aminothiophenols and β-diketones by the use of effective, recycled, cheap and ecologically safe catalysts, such as the montmorillonite clay KSF [113], long-chain ionic liquids [114], sodium dichloroiodate [115], or the Zr-based organometallic catalyst MOF-808 [116]. The mechanism given in Scheme 17 is an example of condensation with the participation of montmorillonite clay [113]. The reaction includes keto-enol Several groups have developed the synthesis of C-2-substituted benzothiazoles 23a-c from 2-aminothiophenols and β-diketones by the use of effective, recycled, cheap and ecologically safe catalysts, such as the montmorillonite clay KSF [113], long-chain ionic liquids [114], sodium dichloroiodate [115], or the Zr-based organometallic catalyst MOF-808 [116]. The mechanism given in Scheme 17 is an example of condensation with the participation of montmorillonite clay [113]. The reaction includes keto-enol tautomerization, the formation of enaminoketone, its cyclization, and the elimination of the enolate. The catalyst is easily separated by simple filtration. The reaction of the acylation of 2-aminothiophenol with acetic acid by the action of direct concentrated solar radiation on heating in the presence of choline chloride has been studied. The yield of product 24a was 60% (Scheme 18, upper route) [117]. The authors note the chemoselectivity of the process of intramolecular acylation. Choline chloride forms hydrogen bonds with the carbonyl oxygen, thus activating the reagent; moreover, it acts as a phase-transfer catalyst and activates the aniline moiety, facilitating the nucleophilic attack and the formation of the intermediate N-acylated product. The method is a good example of green synthesis, as it is metal-free, oxidant-free, and uses choline chloride, which is an inexpensive, biodegradable and recycled catalyst which can be used in water medium.
A similar approach to 2-methylbenzothiazole 24a from aminothiophenol and malonic acid was described [118]. The method is simple, scalable, and gives only small amounts of by-products (Scheme 18, bottom route). The reaction of the acylation of 2-aminothiophenol with acetic acid by the action of direct concentrated solar radiation on heating in the presence of choline chloride has been studied. The yield of product 24a was 60% (Scheme 18, upper route) [117]. The authors note the chemoselectivity of the process of intramolecular acylation. Choline chloride forms hydrogen bonds with the carbonyl oxygen, thus activating the reagent; moreover, it acts as a phase-transfer catalyst and activates the aniline moiety, facilitating the nucleophilic attack and the formation of the intermediate N-acylated product. The method is a good example of green synthesis, as it is metal-free, oxidant-free, and uses choline chloride, which is an inexpensive, biodegradable and recycled catalyst which can be used in water medium. tautomerization, the formation of enaminoketone, its cyclization, and the elimination of the enolate. The catalyst is easily separated by simple filtration. The reaction of the acylation of 2-aminothiophenol with acetic acid by the action of direct concentrated solar radiation on heating in the presence of choline chloride has been studied. The yield of product 24a was 60% (Scheme 18, upper route) [117]. The authors note the chemoselectivity of the process of intramolecular acylation. Choline chloride forms hydrogen bonds with the carbonyl oxygen, thus activating the reagent; moreover, it acts as a phase-transfer catalyst and activates the aniline moiety, facilitating the nucleophilic attack and the formation of the intermediate N-acylated product. The method is a good example of green synthesis, as it is metal-free, oxidant-free, and uses choline chloride, which is an inexpensive, biodegradable and recycled catalyst which can be used in water medium.
A similar approach to 2-methylbenzothiazole 24a from aminothiophenol and malonic acid was described [118]. The method is simple, scalable, and gives only small amounts of by-products (Scheme 18, bottom route). A similar approach to 2-methylbenzothiazole 24a from aminothiophenol and malonic acid was described [118]. The method is simple, scalable, and gives only small amounts of by-products (Scheme 18, bottom route).
A simple one-pot synthesis of 2-substituted benzothiazoles 25a-k by the reaction of acid chlorides or anhydrides with 2-aminothiophenol in the presence of a basic hetero-geneous catalyst KF·Al 2 O 3 was proposed (Scheme 19). The reaction proceeded under mild conditions in high yields, and the catalyst did not lose its activity after 10 times of recycling. No by-products were detected, and the target products were isolated by simple filtration [119]. or a nanocatalyst on mesoporous silica containing bridge groups of N-sulfonic acid (SA PMO) [97]. All reactions were carried out under mild conditions and without solvent.
A simple one-pot synthesis of 2-substituted benzothiazoles 25a-k by the reaction acid chlorides or anhydrides with 2-aminothiophenol in the presence of a basic heterog neous catalyst KF·Al2O3 was proposed (Scheme 19). The reaction proceeded under mi conditions in high yields, and the catalyst did not lose its activity after 10 times of rec cling. No by-products were detected, and the target products were isolated by simple f tration [119]. Scheme 19. Synthesis of 2-substituted benzothiazoles 25a-k from 2-aminothiophenol and acid chl rides or anhydrides in the presence of basic heterogeneous catalyst.
A convenient route to 2-organyl benzothiazoles 26a-k from 2-aminothiophenols an the derivatives of dimethylformamide in moderate to high yields without the use of tox solvents has been reported [92]. The reaction performed in the presence of imidazoliu chloride was shown to be sensitive to temperature: lowering the temperature by 20 ° decreased the yield by six times. The authors assume that the reaction was initiated by th activation of DMF derivatives with imidazolium chloride leading to the intermediate te rahedral compound (A). Its decomposition resulted in the formation of the intermedia  Non-catalyzed cyclocondensation of 2-aminothiophenol with 4-methylbenzald hyde in DMSO at 190 °C affords 2-(4-tolyl)benzothiazole. The latter undergoes a sequen of transformations leading to dendrimers with terminal benzothiazole groups 27a-(Scheme 21). Similar reactions were performed with 4-methylcinnamic acid. Photophys cal investigation of the obtained dendrimers showed a possibility of their use as additiv to sensitized dyes in solar cells [54]. A convenient route to 2-organyl benzothiazoles 26a-k from 2-aminothiophenols and the derivatives of dimethylformamide in moderate to high yields without the use of toxic solvents has been reported [92]. The reaction performed in the presence of imidazolium chloride was shown to be sensitive to temperature: lowering the temperature by 20 • C decreased the yield by six times. The authors assume that the reaction was initiated by the activation of DMF derivatives with imidazolium chloride leading to the intermediate tetrahedral compound ( acid chlorides or anhydrides with 2-aminothiophenol in the presence of a basi neous catalyst KF·Al2O3 was proposed (Scheme 19). The reaction proceeded u conditions in high yields, and the catalyst did not lose its activity after 10 tim cling. No by-products were detected, and the target products were isolated by tration [119]. A convenient route to 2-organyl benzothiazoles 26a-k from 2-aminothiop the derivatives of dimethylformamide in moderate to high yields without the u solvents has been reported [92]. The reaction performed in the presence of im chloride was shown to be sensitive to temperature: lowering the temperatur decreased the yield by six times. The authors assume that the reaction was initi activation of DMF derivatives with imidazolium chloride leading to the interm rahedral compound (A). Its decomposition resulted in the formation of the in  Non-catalyzed cyclocondensation of 2-aminothiophenol with 4-methy hyde in DMSO at 190 °C affords 2-(4-tolyl)benzothiazole. The latter undergoes of transformations leading to dendrimers with terminal benzothiazole gro (Scheme 21). Similar reactions were performed with 4-methylcinnamic acid. P cal investigation of the obtained dendrimers showed a possibility of their use a to sensitized dyes in solar cells [54]. Non-catalyzed cyclocondensation of 2-aminothiophenol with 4-methylbenzaldehyde in DMSO at 190 • C affords 2-(4-tolyl)benzothiazole. The latter undergoes a sequence of transformations leading to dendrimers with terminal benzothiazole groups 27a-c (Scheme 21). Similar reactions were performed with 4-methylcinnamic acid. Photophysical investigation of the obtained dendrimers showed a possibility of their use as additives to sensitized dyes in solar cells [54]. Now, let us turn to the light-induced syntheses of C-2-substituted benzothiazoles. The method of the synthesis of 2-organylbenzothiazoles 28a-s was developed based on the photooxidative cross-coupling of 2-aminothiophenols with α-oxocarboxylic acids under the action of blue UV irradiation in the presence of H2O2 (Scheme 22). The key step of the radical mechanism of the reaction is the formation of the donor acceptor complex between the reagents. Subsequent decarboxylation and intramolecular cyclization of the intermediate adducts afford the target products. α-Ketoacids and 2-aminothiophenols with various functional groups react readily at room temperature in moderate to good yields without the use of photooxidative or metal-based catalysts [103]. Visible light-induced cascade radical cyclization was performed for the synthesis of benzothiazoles possessing CF2/CF3 substituents in the 2-position, 29a-k and 30a-k, in good yield (Scheme 23). The use of Na2CO3 as a reducing agent facilitated mild fluoroalkylation [90]. The visible light-induced reaction of 2-aminothiophenols with aldehydes was proposed as an economic and safe route to a wide series of benzothiazoles, 31, affording the target products in good yields in the absence of transition metal catalysts or other additives (Scheme 24) [104]. The authors proposed a radical mechanism via diaryldisulfide intermediates. The key step of the radical mechanism of the reaction is the formation of the donor acceptor complex between the reagents. Subsequent decarboxylation and intramolecular cyclization of the intermediate adducts afford the target products. α-Ketoacids and 2-aminothiophenols with various functional groups react readily at room temperature in moderate to good yields without the use of photooxidative or metal-based catalysts [103]. Now, let us turn to the light-induced syntheses of C-2-substituted benzothiazoles. The method of the synthesis of 2-organylbenzothiazoles 28a-s was developed based on the photooxidative cross-coupling of 2-aminothiophenols with α-oxocarboxylic acids under the action of blue UV irradiation in the presence of H2O2 (Scheme 22). The key step of the radical mechanism of the reaction is the formation of the donor acceptor complex between the reagents. Subsequent decarboxylation and intramolecular cyclization of the intermediate adducts afford the target products. α-Ketoacids and 2-aminothiophenols with various functional groups react readily at room temperature in moderate to good yields without the use of photooxidative or metal-based catalysts [103]. Visible light-induced cascade radical cyclization was performed for the synthesis of benzothiazoles possessing CF2/CF3 substituents in the 2-position, 29a-k and 30a-k, in good yield (Scheme 23). The use of Na2CO3 as a reducing agent facilitated mild fluoroalkylation [90]. Visible light-induced cascade radical cyclization was performed for the synthesis of benzothiazoles possessing CF 2 /CF 3 substituents in the 2-position, 29a-k and 30a-k, in good yield (Scheme 23). The use of Na 2 CO 3 as a reducing agent facilitated mild fluoroalkylation [90].

Scheme 21. Synthesis of dendrimers with terminal benzothiazole groups 27a-c.
Now, let us turn to the light-induced syntheses of C-2-substituted benzothiazoles. The method of the synthesis of 2-organylbenzothiazoles 28a-s was developed based on the photooxidative cross-coupling of 2-aminothiophenols with α-oxocarboxylic acids under the action of blue UV irradiation in the presence of H2O2 (Scheme 22). The key step of the radical mechanism of the reaction is the formation of the donor acceptor complex between the reagents. Subsequent decarboxylation and intramolecular cyclization of the intermediate adducts afford the target products. α-Ketoacids and 2-aminothiophenols with various functional groups react readily at room temperature in moderate to good yields without the use of photooxidative or metal-based catalysts [103]. Visible light-induced cascade radical cyclization was performed for the synthesis of benzothiazoles possessing CF2/CF3 substituents in the 2-position, 29a-k and 30a-k, in good yield (Scheme 23). The use of Na2CO3 as a reducing agent facilitated mild fluoroalkylation [90]. The visible light-induced reaction of 2-aminothiophenols with aldehydes was proposed as an economic and safe route to a wide series of benzothiazoles, 31, affording the target products in good yields in the absence of transition metal catalysts or other addi-Scheme 23. Synthesis of benzothiazoles 29a-k, 30a-k with CF 2 /CF 3 substituents in the 2-position.
The visible light-induced reaction of 2-aminothiophenols with aldehydes was proposed as an economic and safe route to a wide series of benzothiazoles, 31, affording the target products in good yields in the absence of transition metal catalysts or other additives (Scheme 24) [104]. The authors proposed a radical mechanism via diaryldisulfide intermediates.
A series of benzothiazolamides, 32a-l, possessing antimicrobial and antifungal activity was prepared in high yields via the cyclocondensation of 2-aminothiophenol with diethyl oxalate, the hydrolysis of the formed ethyl benzothiazole-2-carboxylate, and amidation with the amides of 4-nitrophenylalanine in the presence of HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium) and DIPEA (diisopropylethylamine) in DMF (Scheme 25) [28]. Cyclization of 2-aminothiophenol with acetyl chloride affords 2-methylaminobenzothiazole, which, when treated with bromoacetic acid, gives 3-carboxymethyl-2methylbenzothiazolium bromide. The latter enters condensation with aldehydes in acetonitrile in the presence of piperidine as a base to give new chromophores 33a-e containing the benzothiazole moiety and alkyl groups of different chain lengths (Scheme 26). The investigation of photoelectric properties showed that the efficiency of the power transformation for all sensitizers 33a-e increased with the length of the carbon chain [55]. A series of benzothiazolamides, 32a-l, possessing antimicrobial and antifungal activity was prepared in high yields via the cyclocondensation of 2-aminothiophenol with diethyl oxalate, the hydrolysis of the formed ethyl benzothiazole-2-carboxylate, and amidation with the amides of 4-nitrophenylalanine in the presence of HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium) and DIPEA (diisopropylethylamine) in DMF (Scheme 25) [28]. A series of benzothiazolamides, 32a-l, possessing antimicrobial and antifungal activity was prepared in high yields via the cyclocondensation of 2-aminothiophenol with diethyl oxalate, the hydrolysis of the formed ethyl benzothiazole-2-carboxylate, and amidation with the amides of 4-nitrophenylalanine in the presence of HATU (hexafluorophosphate azabenzotriazole tetramethyl uronium) and DIPEA (diisopropylethylamine) in DMF (Scheme 25) [28]. Cyclization of 2-aminothiophenol with acetyl chloride affords 2-methylaminobenzothiazole, which, when treated with bromoacetic acid, gives 3-carboxymethyl-2methylbenzothiazolium bromide. The latter enters condensation with aldehydes in acetonitrile in the presence of piperidine as a base to give new chromophores 33a-e containing the benzothiazole moiety and alkyl groups of different chain lengths (Scheme 26). The investigation of photoelectric properties showed that the efficiency of the power transformation for all sensitizers 33a-e increased with the length of the carbon chain [55]. Cyclization of 2-aminothiophenol with acetyl chloride affords 2-methylaminobenzothiazole, which, when treated with bromoacetic acid, gives 3-carboxymethyl-2-methylbenzothiazolium bromide. The latter enters condensation with aldehydes in acetonitrile in the presence of piperidine as a base to give new chromophores 33a-e containing the benzothiazole moiety and alkyl groups of different chain lengths (Scheme 26). The investigation of photoelectric properties showed that the efficiency of the power transformation for all sensitizers 33a-e increased with the length of the carbon chain [55].
Cyclization of 2-aminothiophenol with acetyl chloride affords 2-methylaminobenzothiazole, which, when treated with bromoacetic acid, gives 3-carboxymethyl-2methylbenzothiazolium bromide. The latter enters condensation with aldehydes in acetonitrile in the presence of piperidine as a base to give new chromophores 33a-e containing the benzothiazole moiety and alkyl groups of different chain lengths (Scheme 26). The investigation of photoelectric properties showed that the efficiency of the power transformation for all sensitizers 33a-e increased with the length of the carbon chain [55].  Disulfides can also be used as starting materials for the synthesis of C-2-substituted benzothiazoles. Thus, 2-alkyl and 2-aryl(hetaryl)benzothiazoles 35a-k have been prepared by the oxidative coupling of (2-aminoaryl)disulfides and primary alcohols in the presence of initiator DTBP (Scheme 28) [120]. The yields decreased with the steric volume of substituent R2 in the molecule of the alcohol. The highest yields were obtained for ethanol and benzyl alcohol. No reaction occurred with methanol or isopropanol. The process was initiated by the decomposition of DTBP on heating to t-BuO radicals, which oxidized the alcohol molecule. The stability of the formed radical plays a decisive role in, e.g., methanol forming an unstable primary radical. On the other hand, only primary alcohols can be used because two hydrogens in the α-position are necessary for radical oxidation. Scheme 28. Oxidative coupling of (2-aminoaryl)disulfides and primary alcohols.
Ecologically friendly, NaSH-promoted condensation of bis(2-aminophenyl)disulfides and aryl-and hetaryl aldehydes in polyethylene glycol with low-energy microwave assistance allowed to obtain 2-substituted benzothiazoles 36a-q in good yield (Scheme 29) [39]. The method is applicable to benzaldehydes with both electron donor and electron acceptor groups. The presence of NaSH facilitates the fast reduction of disulfides to ami- Disulfides can also be used as starting materials for the synthesis of C-2-substituted benzothiazoles. Thus, 2-alkyl and 2-aryl(hetaryl)benzothiazoles 35a-k have been prepared by the oxidative coupling of (2-aminoaryl)disulfides and primary alcohols in the presence of initiator DTBP (Scheme 28) [120]. The yields decreased with the steric volume of substituent R 2 in the molecule of the alcohol. The highest yields were obtained for ethanol and benzyl alcohol. No reaction occurred with methanol or isopropanol. The process was initiated by the decomposition of DTBP on heating to t-BuO radicals, which oxidized the alcohol molecule. The stability of the formed radical plays a decisive role in, e.g., methanol forming an unstable primary radical. On the other hand, only primary alcohols can be used because two hydrogens in the α-position are necessary for radical oxidation. Disulfides can also be used as starting materials for the synthesis of C-2-substituted benzothiazoles. Thus, 2-alkyl and 2-aryl(hetaryl)benzothiazoles 35a-k have been prepared by the oxidative coupling of (2-aminoaryl)disulfides and primary alcohols in the presence of initiator DTBP (Scheme 28) [120]. The yields decreased with the steric volume of substituent R2 in the molecule of the alcohol. The highest yields were obtained for ethanol and benzyl alcohol. No reaction occurred with methanol or isopropanol. The process was initiated by the decomposition of DTBP on heating to t-BuO radicals, which oxidized the alcohol molecule. The stability of the formed radical plays a decisive role in, e.g., methanol forming an unstable primary radical. On the other hand, only primary alcohols can be used because two hydrogens in the α-position are necessary for radical oxidation. Scheme 28. Oxidative coupling of (2-aminoaryl)disulfides and primary alcohols.
Ecologically friendly, NaSH-promoted condensation of bis(2-aminophenyl)disulfides and aryl-and hetaryl aldehydes in polyethylene glycol with low-energy microwave assistance allowed to obtain 2-substituted benzothiazoles 36a-q in good yield (Scheme 29) [39]. The method is applicable to benzaldehydes with both electron donor and electron acceptor groups. The presence of NaSH facilitates the fast reduction of disulfides to ami-Scheme 28. Oxidative coupling of (2-aminoaryl)disulfides and primary alcohols.
Ecologically friendly, NaSH-promoted condensation of bis(2-aminophenyl)disulfides and aryl-and hetaryl aldehydes in polyethylene glycol with low-energy microwave assistance allowed to obtain 2-substituted benzothiazoles 36a-q in good yield (Scheme 29) [39]. The method is applicable to benzaldehydes with both electron donor and electron acceptor groups. The presence of NaSH facilitates the fast reduction of disulfides to aminothiophenols. The latter react with benzaldehydes affording the corresponding Schiff bases. Intramolecular oxidative cyclization accomplishes this process. Scheme 28. Oxidative coupling of (2-aminoaryl)disulfides and primary alcohols.
Ecologically friendly, NaSH-promoted condensation of bis(2-aminophenyl)disulfides and aryl-and hetaryl aldehydes in polyethylene glycol with low-energy microwave assistance allowed to obtain 2-substituted benzothiazoles 36a-q in good yield (Scheme 29) [39]. The method is applicable to benzaldehydes with both electron donor and electron acceptor groups. The presence of NaSH facilitates the fast reduction of disulfides to aminothiophenols. The latter react with benzaldehydes affording the corresponding Schiff bases. Intramolecular oxidative cyclization accomplishes this process. Scheme 29. Synthesis of benzothiazoles 36a-q from diaryldisulfides and aryl-and hetarylaldehydes. Scheme 29. Synthesis of benzothiazoles 36a-q from diaryldisulfides and aryl-and hetarylaldehydes.
α-Ketoacids react with 2,2'-disulfanediyldianilines in the presence of Na 2 S 2 O 5 via condensation with the amino groups and subsequent cyclization by the nucleophilic addition of sulfur to the C=N bond (Scheme 30) [121]. The intermediate disulfides (A) suffer the S-S bond splitting and decarboxylation finally affords C-2-substituted benzothiazoles 37a-p in moderate to excellent yields. The highest yields in the experiment were obtained for electron-withdrawing substituents in the aromatic ring of α-ketoacid. The reaction is metal-free and proceeds with the evolution of ecologically safe CO 2 . The presence of Na 2 S 2 O 5 is required for complete conversion and for obtaining maximal yields of the target products. α-Ketoacids react with 2,2'-disulfanediyldianilines in the presence of Na2S2O5 via condensation with the amino groups and subsequent cyclization by the nucleophilic addition of sulfur to the C=N bond (Scheme 30) [121]. The intermediate disulfides (A) suffer the S-S bond splitting and decarboxylation finally affords C-2-substituted benzothiazoles 37a-p in moderate to excellent yields. The highest yields in the experiment were obtained for electron-withdrawing substituents in the aromatic ring of α-ketoacid. The reaction is metal-free and proceeds with the evolution of ecologically safe CO2. The presence of Na2S2O5 is required for complete conversion and for obtaining maximal yields of the target products. Scheme 30. The synthesis and probable mechanism of formation of benzothiazoles 37a-p by the reaction of 2,2'-disulfanediyldianilines with α-ketoacids.
Very recently, the reaction of ortho-haloanilides with alkali metal sulfides was reported [122]. The reaction proceeds upon heating in DMF in the presence of heterogeneous catalyst MCM-41-NHC-CuI via the CuI-catalyzed substitution of halogen by sulfur, and cyclization with dehydration and regeneration of the catalyst (Scheme 31). A series of C-2substituted benzothiazoles 38 were obtained in good yields. Scheme 30. The synthesis and probable mechanism of formation of benzothiazoles 37a-p by the reaction of 2,2'-disulfanediyldianilines with α-ketoacids.
Very recently, the reaction of ortho-haloanilides with alkali metal sulfides was reported [122]. The reaction proceeds upon heating in DMF in the presence of heterogeneous catalyst MCM-41-NHC-CuI via the CuI-catalyzed substitution of halogen by sulfur, and cyclization with dehydration and regeneration of the catalyst (Scheme 31). A series of C-2-substituted benzothiazoles 38 were obtained in good yields. reaction of 2,2'-disulfanediyldianilines with α-ketoacids.
Very recently, the reaction of ortho-haloanilides with alkali metal sulfides was reported [122]. The reaction proceeds upon heating in DMF in the presence of heterogeneous catalyst MCM-41-NHC-CuI via the CuI-catalyzed substitution of halogen by sulfur, and cyclization with dehydration and regeneration of the catalyst (Scheme 31). A series of C-2substituted benzothiazoles 38 were obtained in good yields. C-2-substituted benzothiazoles can also be prepared by different one-pot multicomponent reactions. Thus, the effective three-component reaction of redox cyclization allowed the authors to obtain a series of 2-arylbenzothiazoles 39 [123,124]. The reaction was easy to handle, catalyzed by cheap copper acetate, tolerated a wide range of functional groups, was scalable, and used readily available reagents: haloanilines, stable non-toxic arylacetic acids or benzyl chlorides, and elemental sulfur (Scheme 32). The yields varied from good to excellent. The key step both in the reaction with arylacetic acids and with benzyl chlorides is the copper-catalyzed formation of diarylsulfides. C-2-substituted benzothiazoles can also be prepared by different one-pot multicomponent reactions. Thus, the effective three-component reaction of redox cyclization allowed the authors to obtain a series of 2-arylbenzothiazoles 39 [123,124]. The reaction was easy to handle, catalyzed by cheap copper acetate, tolerated a wide range of functional groups, was scalable, and used readily available reagents: haloanilines, stable non-toxic arylacetic acids or benzyl chlorides, and elemental sulfur (Scheme 32). The yields varied from good to excellent. The key step both in the reaction with arylacetic acids and with benzyl chlorides is the copper-catalyzed formation of diarylsulfides. An effective and ecologically friendly methodology has been described for the synthesis of C-2-substituted benzothiazoles 40a-l and 41a-c (Scheme 33) [87]. The one-pot three-component reaction of 2-iodoaniline, aryl-or hetaryl aldehydes and thiourea was catalyzed by ferromagnetic catalyst Cu(0)-Fe3O4@SiO2/NH2cel and was carried out with water as the solvent. The catalyst was easily retrieved with a magnet. A large number of products were obtained in good yields, and the electronic effects in the substituents did not affect the course of the reaction. An effective and ecologically friendly methodology has been described for the synthesis of C-2-substituted benzothiazoles 40a-l and 41a-c (Scheme 33) [87]. The one-pot three-component reaction of 2-iodoaniline, aryl-or hetaryl aldehydes and thiourea was catalyzed by ferromagnetic catalyst Cu(0)-Fe 3 O 4 @SiO 2 /NH 2 cel and was carried out with water as the solvent. The catalyst was easily retrieved with a magnet. A large number of products were obtained in good yields, and the electronic effects in the substituents did not affect the course of the reaction.
The alternative metal-free reaction of anilines, elemental sulfur and ethers in the presence of TBHP and KI gives rise to 2-organylbenzothiazoles 42a-r (Scheme 34) [125]. The nature and position of the substituents in the aniline moiety have no substantial effect on the yield of the target products. The reaction with cyclic ethers proceeds with ring opening leading to heterocyclic alcohols 43a-c in good yields. thesis of C-2-substituted benzothiazoles 40a-l and 41a-c (Scheme 33) [87]. The one-pot three-component reaction of 2-iodoaniline, aryl-or hetaryl aldehydes and thiourea was catalyzed by ferromagnetic catalyst Cu(0)-Fe3O4@SiO2/NH2cel and was carried out with water as the solvent. The catalyst was easily retrieved with a magnet. A large number of products were obtained in good yields, and the electronic effects in the substituents did not affect the course of the reaction. The alternative metal-free reaction of anilines, elemental sulfur and ethers in the presence of TBHP and KI gives rise to 2-organylbenzothiazoles 42a-r (Scheme 34) [125]. The nature and position of the substituents in the aniline moiety have no substantial effect on the yield of the target products. The reaction with cyclic ethers proceeds with ring opening leading to heterocyclic alcohols 43a-c in good yields.
The cyclization of anilines is assumed to be initiated by the selective splitting of the C(sp 3 )-H bond in ethers in the presence of TBHP and KI. As a rule, the first step of reactions of this type is the formation of a radical, (here, t-BuO·). The latter is formed by the reaction of TBHP with KI. Similar one-pot reactions leading to 2-hetarylbenzothiazoles from anilines, elemental sulfur and 2-methylquinolines or benzaldehydes have been described [126,127].
A three-component reaction of 2-aminothiophenols, oxalyl chloride and thiols in the presence of n-tetrabutylammonium iodide (TBAI) allowed the authors to obtain a wide series of S-alkyl-and arylbenzothiazol-2-carbothioates 44 (Scheme 35) [30]. It was assumed that TBAI reacted with thiol to give thiolate ion, which attacked oxalyl chloride with the formation of the thioether intermediate entering TBAI-assisted condensation with 2-aminothiophenol to give the target products in 56-80% yields. The investigation of biological activity showed antimicrobial activity and low toxicity of the products. The metal-free assembly of C-2-substituted benzothiazoles 45a-g, 46a-f or 47a-l based on the reaction of arylamines, elemental sulfur and styrenes or arylacetylenes in Nmethylpyrrolidin-2-one (NMP) has been reported (Scheme 36) [128]. The C-S bond was formed by direct thiylation of the C-H bond in aromatic amine with elemental sulfur, acting both as the source of sulfur and the oxidant. The addition of NH4I increased the yield, which was also affected by the nature and position of substituents in the phenyl ring. A possible mechanism for the formation of the C-2-substituted benzothiazoles is given in Scheme 36, using the example of aniline with sulfur and styrene. Aniline reacts with sulfur to give adduct (A), which further reacts with styrene to give polysulfide (B). The latter adds another aniline molecule leading to thioamide (C). The S-S bond in the The cyclization of anilines is assumed to be initiated by the selective splitting of the C(sp 3 )-H bond in ethers in the presence of TBHP and KI. As a rule, the first step of reactions of this type is the formation of a radical, (here, t-BuO·). The latter is formed by the reaction of TBHP with KI.
A three-component reaction of 2-aminothiophenols, oxalyl chloride and thiols in the presence of n-tetrabutylammonium iodide (TBAI) allowed the authors to obtain a wide series of S-alkyland arylbenzothiazol-2-carbothioates 44 (Scheme 35) [30]. It was assumed that TBAI reacted with thiol to give thiolate ion, which attacked oxalyl chloride with the formation of the thioether intermediate entering TBAI-assisted condensation with 2-aminothiophenol to give the target products in 56-80% yields. The investigation of biological activity showed antimicrobial activity and low toxicity of the products. Similar one-pot reactions leading to 2-hetarylbenzothiazoles from anilines, elemental sulfur and 2-methylquinolines or benzaldehydes have been described [126,127].
A three-component reaction of 2-aminothiophenols, oxalyl chloride and thiols in the presence of n-tetrabutylammonium iodide (TBAI) allowed the authors to obtain a wide series of S-alkyl-and arylbenzothiazol-2-carbothioates 44 (Scheme 35) [30]. It was assumed that TBAI reacted with thiol to give thiolate ion, which attacked oxalyl chloride with the formation of the thioether intermediate entering TBAI-assisted condensation with 2-aminothiophenol to give the target products in 56-80% yields. The investigation of biological activity showed antimicrobial activity and low toxicity of the products. The metal-free assembly of C-2-substituted benzothiazoles 45a-g, 46a-f or 47a-l based on the reaction of arylamines, elemental sulfur and styrenes or arylacetylenes in Nmethylpyrrolidin-2-one (NMP) has been reported (Scheme 36) [128]. The C-S bond was formed by direct thiylation of the C-H bond in aromatic amine with elemental sulfur, acting both as the source of sulfur and the oxidant. The addition of NH4I increased the yield, which was also affected by the nature and position of substituents in the phenyl ring. A possible mechanism for the formation of the C-2-substituted benzothiazoles is given in Scheme 36, using the example of aniline with sulfur and styrene. Aniline reacts with sulfur to give adduct (A), which further reacts with styrene to give polysulfide (B). The latter adds another aniline molecule leading to thioamide (C). The S-S bond in the The metal-free assembly of C-2-substituted benzothiazoles 45a-g, 46a-f or 47a-l based on the reaction of arylamines, elemental sulfur and styrenes or arylacetylenes in N-methylpyrrolidin-2-one (NMP) has been reported (Scheme 36) [128]. The C-S bond was formed by direct thiylation of the C-H bond in aromatic amine with elemental sulfur, acting both as the source of sulfur and the oxidant. The addition of NH 4 I increased the yield, which was also affected by the nature and position of substituents in the phenyl ring. A possible mechanism for the formation of the C-2-substituted benzothiazoles is given in Scheme 36, using the example of aniline with sulfur and styrene. Aniline reacts with sulfur to give adduct (A), which further reacts with styrene to give polysulfide (B). The latter adds another aniline molecule leading to thioamide (C). The S-S bond in the latter is split to form thioamide (D) which, after oxidative cyclization, affords the final product. Later, the strategy of a highly atom economical Cu(II)-catalyzed assembly of benzothiazoles from 2-iodoanilines, alkenes and elemental sulfur-avoiding the use of ecologically undesirable thiophenols-was developed by another group [129].

Synthesis of C-2-Substituted Benzothiazoles via the Introduction of Substituents at the 2-Position
A particular class of reactions is the functionalization of the already existing benzothiazole motif at the 2-position. This approach has already led to the synthesis of a large number of compounds including those possessing different pharmacological activity. For example, benzothiazoles are alkylated with acetonitrile at the 2-position in the presence of lithium t-butoxide and dioxane as a cosolvent to give 2-methylbenzothiazoles 48a-e (Scheme 37) [130].
A simple approach to 2-arylbenzothiazoles 49a-i based on the coupling reaction between benzothiazole and arylsulfamates was proposed [131]. The reaction proceeds in the Scheme 36. Synthesis and mechanism of formation of benzothiazoles 45a-g, 46a-f or 47a-l by the reaction of arylamines, sulfur and styrenes or arylacetylenes.
Later, the strategy of a highly atom economical Cu(II)-catalyzed assembly of benzothiazoles from 2-iodoanilines, alkenes and elemental sulfur-avoiding the use of ecologically undesirable thiophenols-was developed by another group [129].

Synthesis of C-2-Substituted Benzothiazoles via the Introduction of Substituents at the 2-Position
A particular class of reactions is the functionalization of the already existing benzothiazole motif at the 2-position. This approach has already led to the synthesis of a large number of compounds including those possessing different pharmacological activity. For example, benzothiazoles are alkylated with acetonitrile at the 2-position in the presence of lithium t-butoxide and dioxane as a cosolvent to give 2-methylbenzothiazoles 48a-e (Scheme 37) [130].
A simple approach to 2-arylbenzothiazoles 49a-i based on the coupling reaction between benzothiazole and arylsulfamates was proposed [131]. The reaction proceeds in the presence of a catalyst and cocatalyst with nickel bromide and 1,10-phenanthroline monohydrate (Scheme 38).

the 2-Position
A particular class of reactions is the functionalization of the already existing benzothiazole motif at the 2-position. This approach has already led to the synthesis of a large number of compounds including those possessing different pharmacological activity. For example, benzothiazoles are alkylated with acetonitrile at the 2-position in the presence of lithium t-butoxide and dioxane as a cosolvent to give 2-methylbenzothiazoles 48a-e (Scheme 37) [130].
A simple approach to 2-arylbenzothiazoles 49a-i based on the coupling reaction between benzothiazole and arylsulfamates was proposed [131]. The reaction proceeds in the  [132,133]. The latter is the benzo-analogue of the natural plant-produced antimicrobial substance phytoalexin inhibiting the growth of parasites. The method is advantageous over other methods of heteroaromatic ring coupling, as it does not require expensive catalysts of air-and moisture-sensitive organometallic reagents, results in high yields, and is scalable. The chemoselective alkylation/arylation of benzothiazoles with aldehydes and benzyl alcohols in the presence of a heterogeneous nanocomposite catalyst and oxidant with graphene oxide-Fe3O4 in polyethylene glycol (Scheme 40) affords 2-alkyl(aryl)-substituted benzothiazole derivatives 52a-u and 53a-g in moderate to excellent yields [134]. The advantages of the method are the absence of noble metals, toxic solvents, easy product isolation, and the possibility of reusing the catalyst without the loss of catalytic activity. The reaction proceeds with the thiazole ring opening and the condensation of the formed aminothiophenol with aldehyde. Then, the formed imine (A) undergoes intramolecular cyclization with the formation of 2-substituted thiazoline (B) and aromatization of the latter by the action of oxidant DIAD (diisopropyl azodicarboxylate).  [132,133]. The latter is the benzo-analogue of the natural plant-produced antimicrobial substance phytoalexin inhibiting the growth of parasites. The method is advantageous over other methods of heteroaromatic ring coupling, as it does not require expensive catalysts of airand moisture-sensitive organometallic reagents, results in high yields, and is scalable.  [132,133]. The latter is the benzo-analogue of the natural plant-produced antimicrobial substance phytoalexin inhibiting the growth of parasites. The method is advantageous over other methods of heteroaromatic ring coupling, as it does not require expensive catalysts of air-and moisture-sensitive organometallic reagents, results in high yields, and is scalable. The chemoselective alkylation/arylation of benzothiazoles with aldehydes and benzyl alcohols in the presence of a heterogeneous nanocomposite catalyst and oxidant with graphene oxide-Fe3O4 in polyethylene glycol (Scheme 40) affords 2-alkyl(aryl)-substituted benzothiazole derivatives 52a-u and 53a-g in moderate to excellent yields [134]. The advantages of the method are the absence of noble metals, toxic solvents, easy product isolation, and the possibility of reusing the catalyst without the loss of catalytic activity. The reaction proceeds with the thiazole ring opening and the condensation of the formed aminothiophenol with aldehyde. Then, the formed imine (A) undergoes intramolecular cyclization with the formation of 2-substituted thiazoline (B) and aromatization of the latter by the action of oxidant DIAD (diisopropyl azodicarboxylate).
The chemoselective alkylation/arylation of benzothiazoles with aldehydes and benzyl alcohols in the presence of a heterogeneous nanocomposite catalyst and oxidant with graphene oxide-Fe 3 O 4 in polyethylene glycol (Scheme 40) affords 2-alkyl(aryl)-substituted benzothiazole derivatives 52a-u and 53a-g in moderate to excellent yields [134]. The advantages of the method are the absence of noble metals, toxic solvents, easy product isolation, and the possibility of reusing the catalyst without the loss of catalytic activity. The reaction proceeds with the thiazole ring opening and the condensation of the formed aminothiophenol with aldehyde. Then, the formed imine (A) undergoes intramolecular cyclization with the formation of 2-substituted thiazoline (B) and aromatization of the latter by the action of oxidant DIAD (diisopropyl azodicarboxylate).
A practical green synthesis of 6-substituted 2-(2-hydroxy(methoxy)phenyl)benzothiazoles 54a-f, including mesylate salts 55a-f, was elaborated (Scheme 41) [15]. The reaction was catalyst-free and used the ecologically safe and cheap solvents of glycerol and acetic acid. The optimization of the reaction conditions, solvents, and the reagents allowed the authors to carry out the reaction with compounds with hydrolytically unstable substituents. The relationship between the structure and biological activity for new compounds was studied, such as 2-hydroxyphenyl-and 2-methoxyphenylbenzothiazole with different substituents in the C-6 position of the benzothiazole fragment. The presence of the nitro or cyano group in the C-6 position of the benzothiazole ring was found to increase the antiproliferative activity. The replacement of the cationic amidine fragment in the C-6 position by the ammonium group led to the increase in antitumor activity against other types of tumor cells. The presence of a hydroxy group in the 2-aryl fragment of 2-arylbenzothiazole molecule considerably improved the antitumor selectivity without affecting the surrounding tissues. A practical green synthesis of 6-substituted 2-(2-hydroxy(methoxy)phenyl)benzothiazoles 54a-f, including mesylate salts 55a-f, was elaborated (Scheme 41) [15]. The reaction was catalyst-free and used the ecologically safe and cheap solvents of glycerol and acetic acid. The optimization of the reaction conditions, solvents, and the reagents allowed the authors to carry out the reaction with compounds with hydrolytically unstable substituents. The relationship between the structure and biological activity for new compounds was studied, such as 2-hydroxyphenyl-and 2-methoxyphenylbenzothiazole with different substituents in the C-6 position of the benzothiazole fragment. The presence of the nitro or cyano group in the C-6 position of the benzothiazole ring was found to increase the antiproliferative activity. The replacement of the cationic amidine fragment in the C-6 position by the ammonium group led to the increase in antitumor activity against other types of tumor cells. The presence of a hydroxy group in the 2-aryl fragment of 2-arylbenzothiazole molecule considerably improved the antitumor selectivity without affecting the surrounding tissues. Various acyl groups were introduced in benzothiazoles in the presence of a Fe(II) triflate catalyst by the reaction of benzothiazole and its derivatives with cyclobutanone oximes (Scheme 42) [135]. A wide spectrum of alkylbenzothiazoloarylketones 56a-k was  A practical green synthesis of 6-substituted 2-(2-hydroxy(methoxy)phenyl)benzothiazoles 54a-f, including mesylate salts 55a-f, was elaborated (Scheme 41) [15]. The reaction was catalyst-free and used the ecologically safe and cheap solvents of glycerol and acetic acid. The optimization of the reaction conditions, solvents, and the reagents allowed the authors to carry out the reaction with compounds with hydrolytically unstable substituents. The relationship between the structure and biological activity for new compounds was studied, such as 2-hydroxyphenyl-and 2-methoxyphenylbenzothiazole with different substituents in the C-6 position of the benzothiazole fragment. The presence of the nitro or cyano group in the C-6 position of the benzothiazole ring was found to increase the antiproliferative activity. The replacement of the cationic amidine fragment in the C-6 position by the ammonium group led to the increase in antitumor activity against other types of tumor cells. The presence of a hydroxy group in the 2-aryl fragment of 2-arylbenzothiazole molecule considerably improved the antitumor selectivity without affecting the surrounding tissues. Various acyl groups were introduced in benzothiazoles in the presence of a Fe(II) triflate catalyst by the reaction of benzothiazole and its derivatives with cyclobutanone oximes (Scheme 42) [135]. A wide spectrum of alkylbenzothiazoloarylketones 56a-k was synthesized with a good selectivity and tolerance to the functional groups. The proposed method was an alternative to the conventional Friedel-Crafts acylation, allowing the Various acyl groups were introduced in benzothiazoles in the presence of a Fe(II) triflate catalyst by the reaction of benzothiazole and its derivatives with cyclobutanone oximes (Scheme 42) [135]. A wide spectrum of alkylbenzothiazoloarylketones 56a-k was synthesized with a good selectivity and tolerance to the functional groups. The proposed method was an alternative to the conventional Friedel-Crafts acylation, allowing the authors to prepare new compounds inaccessible by other methods. The mechanism included several steps: Fe(II)→Fe(III)-induced SET-reduction of cyclobutanone oximes leading to iminyl radical (A) и Fe(III); ring opening in (A) to form the highly reactive cyanoalkyl radical (B); the capture of CO to give radical (C); and the addition to benzothiazole resulting in the radical (D). The oxidation of the latter by Fe(III) with subsequent deprotonation with a base gives alkylhetarylketones 56a-k. authors to prepare new compounds inaccessible by other methods. The mechanism included several steps: Fe(II)→Fe(III)-induced SET-reduction of cyclobutanone oximes leading to iminyl radical (A) и Fe(III); ring opening in (A) to form the highly reactive cyanoalkyl radical (B); the capture of CO to give radical (C); and the addition to benzothiazole resulting in the radical (D). The oxidation of the latter by Fe(III) with subsequent deprotonation with a base gives alkylhetarylketones 56a-k. Scheme 42. Synthesis and mechanism of the formation of alkylbenzothiazolketones 56a-k.

Modification of Substituents in the C-2 Position of Benzothiazoles
The modification of substituents in the C-2 position is a widely used reaction; some examples are considered below. The condensation of N-benzyl-2-methylbenzothiazolium bromide prepared by the alkylation of 2-methylbenzothiazole with benzyl bromide and N-ethylcarbazole dialdehyde gives rise to the formation of the carbazole-benzothiazole hybrid fluorescent probe 57 (Scheme 43) [106]. This fluorophore showed a quick response, in addition to high selectivity and sensitivity in the detection of SO2. Moreover, good biocompatibility and a precise localization in the mitochondria were found. A large series of potentially biologically active drugs, in particular, antitumor agents, based on benzothiazol-2-ylacetonitrile (BTA) has been described [10,11,16]. Below, some examples of the use of this synthon and the products thereof are given. In the synthesized hybrids, the benzothiazole fragment has different substituted heterocyclic rings in the C-2 position, such as thiazole, thiazinane, thiophene, pyrrole, thienopyrimidine, indole, furan, pyridine, chromene, quinoline, triazoloquinoline, triazepinoquinoline, etc. The pyridine or furan hybrids 58 or 59 are formed by the reaction of benzothiazol-2-ylacetonitrile containing an active methylene group with 2-(2,4-dimethoxybenzylidene)malononitrile or ethyl-2-chloro-3-oxobutanoate (Scheme 44) [10]. Scheme 42. Synthesis and mechanism of the formation of alkylbenzothiazolketones 56a-k.

Modification of Substituents in the C-2 Position of Benzothiazoles
The modification of substituents in the C-2 position is a widely used reaction; some examples are considered below. The condensation of N-benzyl-2-methylbenzothiazolium bromide prepared by the alkylation of 2-methylbenzothiazole with benzyl bromide and N-ethylcarbazole dialdehyde gives rise to the formation of the carbazole-benzothiazole hybrid fluorescent probe 57 (Scheme 43) [106]. This fluorophore showed a quick response, in addition to high selectivity and sensitivity in the detection of SO 2 . Moreover, good biocompatibility and a precise localization in the mitochondria were found. authors to prepare new compounds inaccessible by other methods. The mechanism included several steps: Fe(II)→Fe(III)-induced SET-reduction of cyclobutanone oximes leading to iminyl radical (A) и Fe(III); ring opening in (A) to form the highly reactive cyanoalkyl radical (B); the capture of CO to give radical (C); and the addition to benzothiazole resulting in the radical (D). The oxidation of the latter by Fe(III) with subsequent deprotonation with a base gives alkylhetarylketones 56a-k. Scheme 42. Synthesis and mechanism of the formation of alkylbenzothiazolketones 56a-k.

Modification of Substituents in the C-2 Position of Benzothiazoles
The modification of substituents in the C-2 position is a widely used reaction; some examples are considered below. The condensation of N-benzyl-2-methylbenzothiazolium bromide prepared by the alkylation of 2-methylbenzothiazole with benzyl bromide and N-ethylcarbazole dialdehyde gives rise to the formation of the carbazole-benzothiazole hybrid fluorescent probe 57 (Scheme 43) [106]. This fluorophore showed a quick response, in addition to high selectivity and sensitivity in the detection of SO2. Moreover, good biocompatibility and a precise localization in the mitochondria were found. A large series of potentially biologically active drugs, in particular, antitumor agents, based on benzothiazol-2-ylacetonitrile (BTA) has been described [10,11,16]. Below, some examples of the use of this synthon and the products thereof are given. In the synthesized hybrids, the benzothiazole fragment has different substituted heterocyclic rings in the C-2 position, such as thiazole, thiazinane, thiophene, pyrrole, thienopyrimidine, indole, furan, pyridine, chromene, quinoline, triazoloquinoline, triazepinoquinoline, etc. The pyridine or furan hybrids 58 or 59 are formed by the reaction of benzothiazol-2-ylacetonitrile containing an active methylene group with 2-(2,4-dimethoxybenzylidene)malononitrile or ethyl-2-chloro-3-oxobutanoate (Scheme 44) [10]. A large series of potentially biologically active drugs, in particular, antitumor agents, based on benzothiazol-2-ylacetonitrile (BTA) has been described [10,11,16]. Below, some examples of the use of this synthon and the products thereof are given. In the synthesized hybrids, the benzothiazole fragment has different substituted heterocyclic rings in the C-2 position, such as thiazole, thiazinane, thiophene, pyrrole, thienopyrimidine, indole, furan, pyridine, chromene, quinoline, triazoloquinoline, triazepinoquinoline, etc. The pyridine or furan hybrids 58 or 59 are formed by the reaction of benzothiazol-2-ylacetonitrile containing an active methylene group with 2-(2,4-dimethoxybenzylidene)malononitrile or ethyl-2chloro-3-oxobutanoate (Scheme 44) [10].
The reaction of BTA with carbon disulfide gives ketene acetal, which reacts with α-chloroethyl acetate resulting in thiophenebenzothiazole 60. Hydrazinolysis of the latter and condensation of the hydrazide with phthalic or acetic anhydride in the presence of acetic acid results in the corresponding amides 61 and 62 in good yields. The reaction of BTA with phenylisothiocyanate and phenacyl bromide affords the corresponding thiophene derivative 63 (Scheme 45) [10]. Compounds 61 and 62 have shown high antitumor activity to different cell lines. Compound 65 was further functionalized by the reaction of cyclocondensation with formic acid, chloroacetyl chloride, ethyl cyanoacetate, or ethylenediamine to give benzothiazole thienopyrimidine 66a-c or the imidazoline derivative 67 (Scheme 47) [11]. The latter compound, similar to compounds 61 and 62 above, has shown high antitumor activity to different cell lines. Compound 65 was further functionalized by the reaction of cyclocondensation with formic acid, chloroacetyl chloride, ethyl cyanoacetate, or ethylenediamine to give benzothiazole thienopyrimidine 66a-c or the imidazoline derivative 67 (Scheme 47) [11]. The latter compound, similar to compounds 61 and 62 above, has shown high antitumor activity to different cell lines. Compound 65 was further functionalized by the reaction of cyclocondensation with formic acid, chloroacetyl chloride, ethyl cyanoacetate, or ethylenediamine to give benzothiazole thienopyrimidine 66a-c or the imidazoline derivative 67 (Scheme 47) [11]. The latter compound, similar to compounds 61 and 62 above, has shown high antitumor activity to different cell lines.  The iminoquinoline derivative 71 was synthesized by the Knoevenagel reaction using bromosalicyl aldehyde as the carbonyl component and benzothiazol-2-yl acetonitrile, followed by intramolecular cyclization and reflux with hydrazine hydrate in ethanol (Scheme 51) [10]. A series of biologically active compounds was obtained from 2-[3(4)-aminophenyl]benzothiazoles 73 or 74 [17,18,20,29]. Thus, the reaction of (3-aminophenyl)benzothiazole 73 with ethyl acetylacetonate with the subsequent formation of the pyrazole ring by the reaction with hydrazines afforded 2-benzothiazolyl pyrazole derivatives containing hydrazone spacers 75a,b (Scheme 53) [17]. Condensation of the isomeric 4-aminophenylbenzothiazole 74 with aromatic aldehydes or ketones in glacial acetic acid or in the presence of conc. H2SO4 leads to benzothiazoles with the azomethine bonds 76a-p and 76q-s (Scheme 54) [18]. These Schiff bases show anticancer activity and compounds possessing dihydroxy groups with very high inhibitive activity. The cascade multicomponent reaction of product 71 with p-chlorobenzaldehyde and benzothiazol-2-ylacetonitrile in dioxane led to the formation of the triazepine derivative 72 (Scheme 52) [11]. The iminoquinoline derivative 71 was synthesized by the Knoevenagel reaction using bromosalicyl aldehyde as the carbonyl component and benzothiazol-2-yl acetonitrile, followed by intramolecular cyclization and reflux with hydrazine hydrate in ethanol (Scheme 51) [10]. A series of biologically active compounds was obtained from 2-[3(4)-aminophenyl]benzothiazoles 73 or 74 [17,18,20,29]. Thus, the reaction of (3-aminophenyl)benzothiazole 73 with ethyl acetylacetonate with the subsequent formation of the pyrazole ring by the reaction with hydrazines afforded 2-benzothiazolyl pyrazole derivatives containing hydrazone spacers 75a,b (Scheme 53) [17]. Condensation of the isomeric 4-aminophenylbenzothiazole 74 with aromatic aldehydes or ketones in glacial acetic acid or in the presence of conc. H2SO4 leads to benzothiazoles with the azomethine bonds 76a-p and 76q-s (Scheme 54) [18]. These Schiff bases show anticancer activity and compounds possessing dihydroxy groups with very high inhibitive activity. A series of biologically active compounds was obtained from 2-[3(4)-aminophenyl]benzothiazoles 73 or 74 [17,18,20,29]. Thus, the reaction of (3-aminophenyl)benzothiazole 73 with ethyl acetylacetonate with the subsequent formation of the pyrazole ring by the reaction with hydrazines afforded 2-benzothiazolyl pyrazole derivatives containing hydrazone spacers 75a,b (Scheme 53) [17]. The iminoquinoline derivative 71 was synthesized by the Knoevenagel reaction using bromosalicyl aldehyde as the carbonyl component and benzothiazol-2-yl acetonitrile, followed by intramolecular cyclization and reflux with hydrazine hydrate in ethanol (Scheme 51) [10]. The cascade multicomponent reaction of product 71 with p-chlorobenzaldehyde and benzothiazol-2-ylacetonitrile in dioxane led to the formation of the triazepine derivative 72 (Scheme 52) [11]. A series of biologically active compounds was obtained from 2-[3(4)-aminophenyl]benzothiazoles 73 or 74 [17,18,20,29]. Thus, the reaction of (3-aminophenyl)benzothiazole 73 with ethyl acetylacetonate with the subsequent formation of the pyrazole ring by the reaction with hydrazines afforded 2-benzothiazolyl pyrazole derivatives containing hydrazone spacers 75a,b (Scheme 53) [17]. Condensation of the isomeric 4-aminophenylbenzothiazole 74 with aromatic aldehydes or ketones in glacial acetic acid or in the presence of conc. H2SO4 leads to benzothiazoles with the azomethine bonds 76a-p and 76q-s (Scheme 54) [18]. These Schiff bases show anticancer activity and compounds possessing dihydroxy groups with very high inhibitive activity. Condensation of the isomeric 4-aminophenylbenzothiazole 74 with aromatic aldehydes or ketones in glacial acetic acid or in the presence of conc. H 2 SO 4 leads to benzothiazoles with the azomethine bonds 76a-p and 76q-s (Scheme 54) [18]. These Schiff bases show anticancer activity and compounds possessing dihydroxy groups with very high inhibitive activity.
With chloroacetyl chloride, compound 74 forms 2-substituted benzothiazole with chloroacetamide group 77 which, upon the reaction with substituted piperazines, gives 2-aryl benzothiazole derivatives 78a-o possessing anticancer activity. The reaction of 74 with propargyl bromide followed by cyclization of arylazides to the triple bond gives products with the 1,2,3-triazole motif 79a-k in 67-91% yields (Scheme 55) [20]. With chloroacetyl chloride, compound 74 forms 2-substituted benzothiazole with chloroacetamide group 77 which, upon the reaction with substituted piperazines, gives 2aryl benzothiazole derivatives 78a-о possessing anticancer activity. The reaction of 74 with propargyl bromide followed by cyclization of arylazides to the triple bond gives products with the 1,2,3-triazole motif 79a-k in 67-91% yields (Scheme 55) [20]. With primary and secondary amines, compound 77 reacts with the formation of a large library of heterocyclic benzothiazole derivatives 80a-m and 81a-о, for which anticancer activity has been evaluated (Scheme 56) [21]. With chloroacetyl chloride, compound 74 forms 2-substituted benzothiazole with chloroacetamide group 77 which, upon the reaction with substituted piperazines, gives 2aryl benzothiazole derivatives 78a-о possessing anticancer activity. The reaction of 74 with propargyl bromide followed by cyclization of arylazides to the triple bond gives products with the 1,2,3-triazole motif 79a-k in 67-91% yields (Scheme 55) [20]. With primary and secondary amines, compound 77 reacts with the formation of a large library of heterocyclic benzothiazole derivatives 80a-m and 81a-о, for which anticancer activity has been evaluated (Scheme 56) [21]. With primary and secondary amines, compound 77 reacts with the formation of a large library of heterocyclic benzothiazole derivatives 80a-m and 81a-o, for which anticancer activity has been evaluated (Scheme 56) [21].
Using the reaction of the diastereoselective ketene-imine cycloaddition, sixteen new benzothiazole β-lactam conjugates have been synthesized [33]. The reaction was performed by the treatment of (benzothiazol-2-yl)phenols with bromoacetic acid in DMF in the presence of solid K 2 CO 3 . The subsequent reaction of the obtained oxyacetic acids with the Schiff bases in the presence of tosyl chloride gave the target cis-β-lactams 84a-p in yields from 60 to 90% (Scheme 58). The obtained hybrids showed good antimicrobial and antimalarial activity. The presence of the nitrophenyl group at the C-4 atom of the β-lactam ring, or anisyl, tolyl, or naphthyl groups on the N-1 atom of the β-lactam ring enhances the antimicrobial activity. The synthesis of azo-linked-substituted benzothiazoles 82 and 83 in good yield by the diazotation of 2-(5'-amino-2'-hydroxyphenyl)benzothiazole was reported [32]. Diazotation was performed under the usual conditions with subsequent treatment with N,Ndibutyl-4-phenylthiazole-2-amine or 3-(diethylamino)phenol in acidic medium upon cooling (Scheme 57). The antibacterial activity of the obtained products was investigated. Using the reaction of the diastereoselective ketene-imine cycloaddition, sixteen new benzothiazole β-lactam conjugates have been synthesized [33]. The reaction was performed by the treatment of (benzothiazol-2-yl)phenols with bromoacetic acid in DMF in the presence of solid K2CO3. The subsequent reaction of the obtained oxyacetic acids with the Schiff bases in the presence of tosyl chloride gave the target cis-β-lactams 84a-p in yields from 60 to 90% (Scheme 58). The obtained hybrids showed good antimicrobial and antimalarial activity. The presence of the nitrophenyl group at the C-4 atom of the β- Using the reaction of the diastereoselective ketene-imine cycloaddition, sixteen new benzothiazole β-lactam conjugates have been synthesized [33]. The reaction was performed by the treatment of (benzothiazol-2-yl)phenols with bromoacetic acid in DMF in the presence of solid K2CO3. The subsequent reaction of the obtained oxyacetic acids with the Schiff bases in the presence of tosyl chloride gave the target cis-β-lactams 84a-p in yields from 60 to 90% (Scheme 58). The obtained hybrids showed good antimicrobial and antimalarial activity. The presence of the nitrophenyl group at the C-4 atom of the β- The introduction of 2-(4-hydroxyphenyl)benzothiazole in the reaction with propargyl bromide in the presence of a base affords 2-(4-propargyloxyphenyl)benzothiazole, which enters cycloaddition reactions with various azides in the presence of copper fluorapatite, leading to benzothiazole-triazole hybrid molecules 85a-t (Scheme 59) [22]. The introduction of 2-(4-hydroxyphenyl)benzothiazole in the reaction with propargyl bromide in the presence of a base affords 2-(4-propargyloxyphenyl)benzothiazole, which enters cycloaddition reactions with various azides in the presence of copper fluorapatite, leading to benzothiazole-triazole hybrid molecules 85a-t (Scheme 59) [22]. Scheme 58. Synthesis of benzothiazole β-lactam conjugates 84a-p.
As mentioned above, a number of hydroxyl-derivatives of benzothiazole demonstrate fluorescent properties. For example, the synthesis of the benzothiazole-based watersoluble biochemosensor 86 used for the detection of intracell zinc and aluminum ions has been described [64]. For this, 3-(benzo[d]thiazol-2-yl)-2-hydroxy-5-methylbenzaldehyde is prepared by successive treatment of hydroxymethylphenylbenzothiazole with trifluoroacetic acid and diaminomalononitrile in the presence of catalytic amounts of acetic acid in dry ethanol (Scheme 60). Scheme 59. Synthesis of polyfunctional derivatives of benzothiazole 85a-t.
As mentioned above, a number of hydroxyl-derivatives of benzothiazole demonstrate fluorescent properties. For example, the synthesis of the benzothiazole-based water-soluble biochemosensor 86 used for the detection of intracell zinc and aluminum ions has been described [64]. For this, 3-(benzo[d]thiazol-2-yl)-2-hydroxy-5-methylbenzaldehyde is prepared by successive treatment of hydroxymethylphenylbenzothiazole with trifluoroacetic acid and diaminomalononitrile in the presence of catalytic amounts of acetic acid in dry ethanol (Scheme 60). Another green and efficient approach to luminophores is mechanochemical, solventfree synthesis [65]. A mixture of 2-(2-hydroxyphenyl)benzothiazole, hexamethylenetetramine, trifluoroacetic acid and silica gel was thoroughly grinded for 3 h. The obtained product was purified by chromatography and grinded with benzophenone hydrazone for 0.5 h. The synthesized dye 87 (Scheme 61) can be used for the detection of Cu 2+ both in solution and in the solid phase. Another green and efficient approach to luminophores is mechanochemical, solventfree synthesis [65]. A mixture of 2-(2-hydroxyphenyl)benzothiazole, hexamethylenetetramine, trifluoroacetic acid and silica gel was thoroughly grinded for 3 h. The obtained product was purified by chromatography and grinded with benzophenone hydrazone for 0.5 h. The synthesized dye 87 (Scheme 61) can be used for the detection of Cu 2+ both in solution and in the solid phase.
The syntheses based on the hydroxyphenyl derivatives of benzothiazole were reported as fluorescent probes 88a-c for the detection of esterase in curing various diseases [60,66], and trace amounts of Hg 2+ [67], Cu 2+ and S 2ions [68] were found (Scheme 62).
Another green and efficient approach to luminophores is mechanochemical, solventfree synthesis [65]. A mixture of 2-(2-hydroxyphenyl)benzothiazole, hexamethylenetetramine, trifluoroacetic acid and silica gel was thoroughly grinded for 3 h. The obtained product was purified by chromatography and grinded with benzophenone hydrazone for 0.5 h. The synthesized dye 87 (Scheme 61) can be used for the detection of Cu 2+ both in solution and in the solid phase. The syntheses based on the hydroxyphenyl derivatives of benzothiazole were reported as fluorescent probes 88a-c for the detection of esterase in curing various diseases [60,66], and trace amounts of Hg 2+ [67], Cu 2+ and S 2-ions [68] were found (Scheme 62). Nitrophenyl 2-(2-hydroxyphenyl)benzothiazole derivatives with -Ar-, -Ar-C=Cand -Ar-C≡C-linkers have been synthesized by the Suzuki, Heck, and Sonogashira reactions, respectively (Scheme 63) [136]. The presence of the strong electron acceptor group 4-NO2C6H4 facilitates a charge transfer and affects the photophysical properties of the molecules. It also facilitates various intermolecular interactions. In the Heck reaction, the substrate was first acetylated with acetic anhydride, and the formed acetate was introduced to the reaction with (E)-4-nitrostyrene to obtain the acetate-protected product. Further deprotection under alkaline conditions gave the target product d-HBT-NO2. To investigate the fluorescent properties of the products, they were converted to the corresponding methoxy derivatives by the action of methyl iodide. Nitrophenyl 2-(2-anisyl)benzothiazole 89b was found to be most promising for further investigation. product was purified by chromatography and grinded with benzophenone hydrazone for 0.5 h. The synthesized dye 87 (Scheme 61) can be used for the detection of Cu 2+ both in solution and in the solid phase. The syntheses based on the hydroxyphenyl derivatives of benzothiazole were reported as fluorescent probes 88a-c for the detection of esterase in curing various diseases [60,66], and trace amounts of Hg 2+ [67], Cu 2+ and S 2-ions [68] were found (Scheme 62). Nitrophenyl 2-(2-hydroxyphenyl)benzothiazole derivatives with -Ar-, -Ar-C=Cand -Ar-C≡C-linkers have been synthesized by the Suzuki, Heck, and Sonogashira reactions, respectively (Scheme 63) [136]. The presence of the strong electron acceptor group 4-NO2C6H4 facilitates a charge transfer and affects the photophysical properties of the molecules. It also facilitates various intermolecular interactions. In the Heck reaction, the substrate was first acetylated with acetic anhydride, and the formed acetate was introduced to the reaction with (E)-4-nitrostyrene to obtain the acetate-protected product. Further deprotection under alkaline conditions gave the target product d-HBT-NO2. To investigate the fluorescent properties of the products, they were converted to the corresponding methoxy derivatives by the action of methyl iodide. Nitrophenyl 2-(2-anisyl)benzothiazole 89b was found to be most promising for further investigation. Nitrophenyl 2-(2-hydroxyphenyl)benzothiazole derivatives with -Ar-, -Ar-C=Cand -Ar-C≡C-linkers have been synthesized by the Suzuki, Heck, and Sonogashira reactions, respectively (Scheme 63) [136]. The presence of the strong electron acceptor group 4-NO 2 C 6 H 4 facilitates a charge transfer and affects the photophysical properties of the molecules. It also facilitates various intermolecular interactions. In the Heck reaction, the substrate was first acetylated with acetic anhydride, and the formed acetate was introduced to the reaction with (E)-4-nitrostyrene to obtain the acetate-protected product. Further deprotection under alkaline conditions gave the target product d-HBT-NO 2 . To investigate the fluorescent properties of the products, they were converted to the corresponding methoxy derivatives by the action of methyl iodide. Nitrophenyl 2-(2-anisyl)benzothiazole 89b was found to be most promising for further investigation. The Pd(PPh3)4-catalyzed Suzuki coupling of 2-(benzothiazol-2-yl)-5-bromophenol and commercially available carboxylic acids gave three positional isomers 90a-c (Scheme 64) [69]. The products showed strong emission in both solid and aggregated states and a low emission in solvents of different polarities. The Pd(PPh3)4-catalyzed Suzuki coupling of 2-(benzothiazol-2-yl)-5-bromophenol and commercially available carboxylic acids gave three positional isomers 90a-c (Scheme 64) [69]. The products showed strong emission in both solid and aggregated states and a low emission in solvents of different polarities. Benzothiazole-2-carbaldehyde was used for the synthesis of new anti-HIV drug biotin-BMMP 91 [37]. First, the aldehyde was quantitatively reduced with NaBH4 to the corresponding alcohol, which was brominated with PBr3. The bromine atom in the formed 2-(bromomethyl)benzothiazole was replaced by pyrimidine thiol, as shown in Scheme 65. Subsequent hydrazinolysis and the EDC-mediated conjugation of primary amine with biotine gave the target biotine-BMMP in 96% yield. Benzothiazole-2-carbaldehyde was used for the synthesis of new anti-HIV drug biotin-BMMP 91 [37]. First, the aldehyde was quantitatively reduced with NaBH 4 to the corresponding alcohol, which was brominated with PBr 3 . The bromine atom in the formed 2-(bromomethyl)benzothiazole was replaced by pyrimidine thiol, as shown in Scheme 65. Subsequent hydrazinolysis and the EDC-mediated conjugation of primary amine with biotine gave the target biotine-BMMP in 96% yield. 2-Acetylbenzothiazole is often used for the synthesis of hybrid molecules. Benzothiazoles containing thieno[2,3-b]pyridine moieties 92a and 92b were obtained in two steps: the bromination of 2-acetylbenzothiazole; and cyclization with mercaptonicotine nitrile (Scheme 66) [137]. 2-Acetylbenzothiazole has also been used for the synthesis of thiazole-, benzothiazole-, and benzofuran-containing molecules, as well as bis-benzothiazole derivatives. The main advantage of these reactions is their easy handling and cheap starting materials [105]. The transformations leading finally to benzothiazoles 93a-c with ethylidenehydra- 2-Acetylbenzothiazole is often used for the synthesis of hybrid molecules. Benzothiazoles containing thieno[2,3-b]pyridine moieties 92a and 92b were obtained in two steps: the bromination of 2-acetylbenzothiazole; and cyclization with mercaptonicotine nitrile (Scheme 66) [137]. 2-Acetylbenzothiazole has also been used for the synthesis of thiazole-, benzothiazole-, and benzofuran-containing molecules, as well as bis-benzothiazole derivatives. The main advantage of these reactions is their easy handling and cheap starting materials [105]. The transformations leading finally to benzothiazoles 93a-c with ethylidenehydrazinyl linkers are shown in Scheme 67. The components of condensation were prepared by 2-Acetylbenzothiazole has also been used for the synthesis of thiazole-, benzothiazole-, and benzofuran-containing molecules, as well as bis-benzothiazole derivatives. The main advantage of these reactions is their easy handling and cheap starting materials [105]. The transformations leading finally to benzothiazoles 93a-c with ethylidenehydrazinyl linkers are shown in Scheme 67. The components of condensation were prepared by the reaction of 2-acetylbenzothiazole with thiosemicarbazide or with bromine. The subsequent reactions of compounds A and B gave the target hybrid molecules. 2-Bromacetyl benzothiazole reacts with mono-and bis-N-amino-2-mercaptotriazoles to give hybrid molecules 94a,b and 95a-d with one or two triazolothiadiazine moieties (Scheme 68) [105]. In a similar way, 2-bromacetyl benzothiazole with bis(thiosemicarbazones) affords hybrid molecules 96a-c linked by the aliphatic spacer via phenoxy groups (Scheme 69) [105]. 2-Bromacetyl benzothiazole reacts with mono-and bis-N-amino-2-mercaptotriazoles to give hybrid molecules 94a,b and 95a-d with one or two triazolothiadiazine moieties (Scheme 68) [105]. In a similar way, 2-bromacetyl benzothiazole with bis(thiosemicarbazones) affords hybrid molecules 96a-c linked by the aliphatic spacer via phenoxy groups (Scheme 69) [105]. In a similar way, 2-bromacetyl benzothiazole with bis(thiosemicarbazones) affords hybrid molecules 96a-c linked by the aliphatic spacer via phenoxy groups (Scheme 69) [105].
Condensation of benzothiazole-2-carbohydrazide with 1H-indole-3-carbaldehydes gives rise to the formation of N-acylhydrazone derivatives 97a-e possessing antitumor activity (Scheme 70) [19]. The products are shown to exist as the E-diastereomers. The method is characterized by mild conditions, high yields, and easy handling. Scheme 68. Synthesis of benzothiazoles with triazolothiadiazine fragments 94a,b and 95a-d.

Conclusions
In summary, the versatile range of synthetic approaches to the C-2 derivatives of benzothiazole developed in the last five years is indicative of the relentless interest in this heterocycle, which is very promising from both a synthetic and biological point of view. In the present review, the methods of synthesis of the title compounds were divided into: (i) intra-and (ii) intermolecular assembling of the benzothiazole ring, (iii) the introduction of substituents at the 2-position, and (iv) the functionalization of the phenylene fragment. Among them, those including the thiazole ring closure and the modification of substituents at the C-2 position were dominant. Along with traditional multistep synthetic methods, new ecologically friendly atom economy one-pot procedures have been developed, which are the basis of modern organic synthesis. For the most interesting processes, only tentative mechanisms are given. Recent studies in this field have allowed the discovery of new C-2-substituted derivatives of benzothiazole and proven them to be good candidates for numerous drugs with various types of biological activity. Their pharmacological and biological activity strongly depend on the nature and position of the substituents, both in the benzene ring of the benzothiazole cycle and in the heterocycles formed by the functionalization of benzothiazole. The authors hope that this review will help the development of the targeted synthesis of benzothiazoles and their analogues. Funding: This research received no external funding.

Conclusions
In summary, the versatile range of synthetic approaches to the C-2 derivatives of benzothiazole developed in the last five years is indicative of the relentless interest in this heterocycle, which is very promising from both a synthetic and biological point of view. In the present review, the methods of synthesis of the title compounds were divided into: (i) intra-and (ii) intermolecular assembling of the benzothiazole ring, (iii) the introduction of substituents at the 2-position, and (iv) the functionalization of the phenylene fragment. Among them, those including the thiazole ring closure and the modification of substituents at the C-2 position were dominant. Along with traditional multistep synthetic methods, new ecologically friendly atom economy one-pot procedures have been developed, which are the basis of modern organic synthesis. For the most interesting processes, only tentative mechanisms are given. Recent studies in this field have allowed the discovery of new C-2-substituted derivatives of benzothiazole and proven them to be good candidates for numerous drugs with various types of biological activity. Their pharmacological and biological activity strongly depend on the nature and position of the substituents, both in the benzene ring of the benzothiazole cycle and in the heterocycles formed by the functionalization of benzothiazole. The authors hope that this review will help the development of the targeted synthesis of benzothiazoles and their analogues.