Isothiazoles in the Design and Synthesis of Biologically Active Substances and Ligands for Metal Complexes

Abstract The chemistry of isothiazoles is being intensively developed, which is evidenced by the wide range of selective transformations involving the isothiazole heterocycle and the high biological activity of its derivatives that can be used as effective new drugs and plant protection chemicals. Some representatives of isothiazoles have proven to be synergists of bioactive substances, which opens the way to lower the doses of drugs used and is especially important in cancer chemotherapy. In the framework of the present review, the accomplishments in the chemistry of isothiazoles over the past 18 years are examined, whilst current strategies for the synthesis of isothiazole-containing molecules and key directions of studies in this field of heterocyclic chemistry are discussed. Considerable attention is paid to chlorinated isothiazoles and strategies for their use in the synthesis of biologically active substances. In addition, a comprehensive review of existing literature in the field of metal complexes of isothiazoles is given, including the results and prospects for the practical use of isothiazole–metal complexes as catalysts for cross-coupling reactions in aqueous and aqueous–alcoholic media (‘green chemistry’). 1 Introduction 2 Synthesis by Ring-Forming Reactions 2.1 Intramolecular Cyclization 2.2 (4+1)-Heterocyclization 2.3 (3+2)-Heterocyclization 2.4 Syntheses by Ring Transformations 3 Isothiazoles by Ring Functionalization Reactions: Nucleophilic Substitution, Cross-Coupling and Side-Chain Functionalization 4 Selected Syntheses of Biologically Active Isothiazole Derivatives 5 Isothiazoles in the Synthesis of Transition-Metal Complexes and in Metal-Complex Catalysis 6 Conclusion


Introduction
The search for new chemical compounds with useful properties and the development of rational ways to synthesize them are priority tasks in chemical science, with the synthesis of biologically active chemical compounds for medicine and agriculture being of particular importance. In this respect, isothiazole derivatives, which have demonstrated high potential in the design and synthesis of a wide range of biologically active substances, are of great interest. Among natural bioregulators, isothiazole-containing compounds are present in only a few examples: the phytoalexins (brassilexin 1 and sinalexin), 2 a prostaglandin release inhibitor (pronkodin A), 3 and a cytotoxin (aulosirazol). 4 However, this does not impede the use of the isothiazole nucleus in the creation of a wide variety of bioactive substances; for example, compounds exhibiting anti-poliovirus activity have been synthesized. 5 Promising compounds for the treatment of Parkinson's disease have also been identified, 6 and recently, derivatives suitable for cancer [7][8][9][10][11][12] and diabetes [13][14][15] therapy have been obtained, as well as microbicides. 16,17 The isothiazole heterocycle in microbicides can protect the molecule from the action of enzymes, 18,19 thereby extending the time of the molecule's action, which in turn makes it possible to administer additional doses of the drug less frequently. A promising class of isothiazole-containing inhibitors of the nuclear bile acid receptor FXR has been found, representatives of which can be used in the treatment of liver diseases. 20 Some isothiazoles can be successfully used to create competitive antagonists of insect GABA receptors, 21 and among the isothiazoles, effective plant growth regulators 22 and fungicides 23,24 have been found.

Review Syn thesis
In a few reports, isothiazoles have been studied for possible use as ligands for metal complexes. At the same time, despite the fact that metal complexes in general have proven themselves useful in creating a wide range of new technologies and biologically active substances, ways to apply isothiazole complexes in practice have rarely been investigated. Some recent publications, in which the promise of using metal complexes of isothiazole for the catalysis of organic reactions and the development of pesticides has been shown, [25][26][27] are the exception.
The above facts demonstrate the high potential of using isothiazole heterocycles in the design and synthesis of compounds for different purposes and indicate broad prospects for the further development of isothiazole chemistry, especially coordination chemistry. Within the framework of the present review, achievements in isothiazole chemistry over the past 18 years will be covered, and references from previous years will be mentioned only to create a holistic picture of the recent research progress in this field.
This review deliberately does not include data on isothiazolinones, 1,1-isothiazoledioxides, and dihydroisothiazoles, and only some examples related to condensed isothiazole-containing systems are considered. This is due to the fact that, in our opinion, such compounds, although being related, differ significantly in their chemical properties from 1,2-thiazole, and a consideration of their chemical transformations as well as their practical use would lead to a significant increase in the volume of this paper and distract from the subject being reviewed. However, special attention is paid to halogen-containing isothiazoles, and in particular, chlorinated isothiazoles, which are convenient synthetic building blocks that allow the ability to obtain a wide variety of substituted isothiazoles capable of acting both as biologically active substances and as ligands for metal complexes.
In the general context of the chemistry of heterocyclic compounds, data on the chemical properties of isothiazoles are presented in review articles, [28][29][30] whilst isothiazoles have been directly reviewed, [31][32][33][34] and covered in a monograph 35 devoted to biologically active isothiazoles. There are also reports summarizing data on isothiazole-ring-containing compounds in crop protection, 36 the involvement of the isothiazole core in cross-coupling reactions, 37 and [4+2] cycloadditions of isothiazole derivatives. 38 There are a significant number of methods for isothiazole synthesis, and so in order to present the material consistently as well as to form a holistic view of isothiazole chemistry, it would be rational to first consider the approaches to isothiazole cycle design, highlighting the main synthetic strategies. Next, some methods for the functionalization of isothiazoles will be reviewed, and after that, targeted syntheses of biologically active agents that are promising for practical use will be considered. The available information on metal complexes with isothiazole ligands is considered in the final part of the literature review, and will, in our opinion, provide a comprehensive picture of developments in the field of isothiazole metal complexes, including information that has escaped the attention of other authors for one reason or another.

Synthesis by Ring-Forming Reactions
Different approaches can be used to classify the methods for producing isothiazoles, and the classification proposed herein by us is based on retrosynthetic analysis. This allows us to build a consistent and logical understanding of the approaches to the production of substituted isothiazoles, and in some cases, to provide the most rational methods for their synthesis. However, the predictive efficiency of this retrosynthetic classification is low in the case of complex reactions with an unobvious mechanism, as the proposed classification does not always reflect the true mechanism of the reaction. Yet, it does allow us to visualize the possible conditions for the preparation of isothiazoles, representing the formation of an isothiazole ring from fragments containing a certain number of atoms. It certainly does not cover all possible methods for the preparation of substituted isothiazoles, but it reflects the key stages of most approaches to their synthesis. Overall, retrosynthetic analysis allows us to distinguish four rational approaches for the formation of the isothiazole ring.

Intramolecular Cyclization
An example of such an approach is the synthesis of substituted isothiazoles 1 by forming an S-N bond in an S-C-C-C-N fragment via oxidative cyclization of substituted 3aminopropenethiones 2 under the action of various reagents. The classic version of this approach uses iodine; 39 however, methods using other oxidizing agents, such as hydrogen peroxide, have recently become very popular (Scheme 1). 40,41 Hydrogen peroxide, in particular, was used in the formation of the isothiazole nucleus at the penultimate stage in the synthesis of a series of allosteric antagonists of the mGluR1 receptor, and which are promising compounds for the treatment of various pain syndromes. 40 Scheme 1 Synthesis of isothiazoles through oxidative cyclization of substituted 3-aminopropenethiones

Review Syn thesis
Along with iodine, bromine can be used for effective oxidative cyclization. Thus, the isothiazoles 4, which are inhibitors of hepatitis C polymerase NS5B as well as precursors of the inhibitors of the important cancer therapy kinases Chk2 and MEK1, have been synthesized by oxidizing N-substituted propanethioamides with molecular bromine in ethyl acetate (Scheme 2). [42][43][44] Scheme 2 Bromine as the efficient reagent for cyclization of 3-aminopropenethiones From a preparative point of view, a promising variation of this approach is the oxidation of isothiazole precursors without the use of a solvent. Thus, it has been shown that the solvent-free oxidative cyclization of 3-aminopropenethiones 5 can be carried out by using chromium trioxide supported on silica gel (Scheme 3). 45 It should be noted that the yields of the corresponding 4-cyanoisothiazoles 6 did not depend on whether the reaction was performed at room temperature for 2-3 hours, or for 1-2 minutes under microwave irradiation.

Scheme 3 Oxidative ring closure of 3-aminopropenethiones under CrO 3 /SiO 2 system action
The closure of the C-N-S-C-C fragment with the formation of a C-C bond can serve as another interesting example of intramolecular cyclization. Using this approach, the formation of an isothiazole ring in the synthesis of the VEGFR1 and VEGFR2 inhibitors was carried out. 46 The intramolecular condensation of an activated methylene fragment with a cyano group in compounds 7 led to isothiazoles 8, of which further directed modification allowed the target compounds to be obtained (Scheme 4).
As an important example of the formation of the isothiazole nucleus by the closure of a five-membered fragment, a recently proposed method for the synthesis of reactive 3chloroisothiazole (9) should be mentioned. The 3,3′-disulfanyldipropanoic acid diamide 10 can be cyclized to give 3chloroisothiazole (9) by the action of phosphorus oxychloride in toluene (Scheme 5). 47 Scheme 5 Preparation of 3-chloroisothiazole from the 3,3′-disulfanyldipropanoic acid diamide

(4+1)-Heterocyclization
In the framework for this approach, we can consider the heterocyclization of synthetic equivalents of synthons, which are formed when one atom is removed from the isothiazole ring, with the synthetic equivalents of the corresponding atom. The most relevant examples of the heterocyclization of compounds corresponding to synthons with one heteroatom removed from a 1,2-thiazole ring are given below.
Recently, an original method for producing substituted furo [2,3-c]isothiazoles 11 from 2-[amino(3-aryl-2-cyanooxiran-2-yl)methylene]malononitriles 12 in an aqueous dioxane medium with sodium thiocyanate as a sulfur donor was described (Scheme 6). 48 It is noteworthy that in previous studies the only proposed method for the synthesis of furo [2,3-c]isothiazoles was via intramolecular nucleophilic substitution with the participation of azide and thione fragments. 49,50 It was found that an S 2 Cl 2 molecule can act as a sulfur donor in the synthesis of isothiazoles, as was shown when preparing dinitrobenzo[c]isothiazole 13 from 2-amino-4,6dinitrotoluene (14) (Scheme 7). 51 The key value of the

Review Syn thesis
nature of the base used in the first stage of the reaction was revealed: when N-ethyldiisopropylamine or triethylamine were used individually, the yield of the desired isothiazole 13 did not exceed 18%. However, with the sequential introduction of 1,4-diazabicyclo[2.2.2]octane (DABCO), and then triethylamine, a 90% yield of isothiazole 13 was achieved.
A recently proposed method for the synthesis of 3,4-dichloroisothiazole-5-carbonitrile (15) from succinonitrile (16), sulfur, and chlorine gas is of considerable industrial interest (Scheme 8). 52 The method avoids the use of aprotic polar solvents such as DMF, which increase the cost of production and at the same time increase the environmental hazards. Nitrile 15 is not only a representative of a reactive class of chlorinated isothiazoles but is also a precursor of 3,4-dichloroisothiazole-5-carboxylic acid 2-cyanoanilide, also known as isotianil, a commercial fungicide.

Scheme 9 A route to 3,5-diarylisothiazoles via the cyclization of ketimines
A new protocol for the synthesis of 3,5-disubstituted/annulated isothiazoles 19 utilizing -keto dithioesters/-keto thioamides 20 and NH 4 OAc under metal-free conditions was reported in 2016 (Scheme 10). 54 The strategic (4+1) annulation initiated by NH 4 OAc is carboneconomic and relies on a sequential imine formation/ cyclization/aerial oxidation cascade forming consecutive C-N and S-N bonds in one pot. Scheme 10 Use of -keto thioesters for 3,5-disubstituted isothiazole synthesis Substituted isothiazoles 21 were able to be isolated as minor products when -keto dithioesters 22 were reacted with ammonia, which also acts as a donor of the nitrogen atom to construct a 1,2-thiazole heterocycle. Additionally, it was found that copper acetate promotes formation of the isothiazole heterocycle (Scheme 11). 55 Scheme 11 Short pathway to 5-thioisothiazoles

(3+2)-Heterocyclization
This approach involves the interaction of two chemical compounds that act as suppliers of diatomic and triatomic fragments to form an isothiazole ring.
Recently, a series of 4-arylisothiazoles 24, as inhibitors of the detoxification of the isothiazole-containing brassilexin fungicide in L. maculans fungus, was synthesized using this approach. Thus, the corresponding ,-unsaturated aldehydes 23 were introduced into the reaction with ammonium thiocyanate in dimethylformamide to give the 4arylisothiazoles 24 (Scheme 12). 56 The ammonium thiocyanate in the reaction acts as a donor of the N-S fragment.

Review Syn thesis
Scheme 13 3-Chloroacrylaldehydes in the synthesis of arylisothiazoles The 1,3-dipolar cycloaddition reaction, also known as the Huisgen cycloaddition, represents another method that can be used for isothiazole cycle formation and should be mentioned within the framework of the regarded approach. The reaction of functionalized acetylenes with nitrile sulfides-reactive dipoles generated from 2-oxo-1,3,4-oxathiazoles in aprotic polar solvents such as chlorobenzene and toluene-can serve as an example. In particular, 3-phenylisothiazol-5-carboxylic acid 27a and 3-phenylisothiazole-4carboxylic acid 27b were obtained from phenyloxathiazolone 28 by this method (Scheme 14), and the synthesized products showed low in vitro cytotoxicity along with the ability to protect cells from being infected with HIV-1. 59

Scheme 14
The cycloaddition reaction between 2-oxo-1,3,4-oxathiazole and methyl propiolate The efficiency of using microwave irradiation in such reactions has been demonstrated. This method allows avoiding long reaction times and, in some cases, reduces the amount of by-products and increases the yields of the target compounds. 60 Thus, phenyloxothiazolone 29 was reacted with dimethyl acetylenedicarboxylate (DMAD) in chloroform under microwave irradiation to form adduct 30 in a yield of 56%, while the reaction with propiolic acid ethyl ester (EP) for 10 minutes resulted in a mixture of regioisomeric isothiazoles 31a and 31b with a total yield of 48% (Scheme 15). The authors noted that a low level of regioselectivity was a common factor for reactions of nitrile sulfides, in contrast to reactions of nitrile oxides, which led to isoxazole-5-carboxylates as the main products. This effect is usually attributed to a higher degree of HOMO-dipole control for nitrile sulfide reactions.
Finally, a very interesting and original example of (3+2)heterocyclization is the recently proposed method of asymmetric synthesis of condensed isothiazoles 32 through a copper-catalyzed direct asymmetric conjugate addition of allyl cyanide (33) to ,-unsaturated thioamides 34 (Scheme 16). 61

Scheme 16 An example of an asymmetric cyclocondensation resulting in isothiazoles
It is important to note that the yield of the target isothiazoles 32a-d increased with the introduction of preliminary isolated products of the allyl cyanides addition 35 to ,-unsaturated thioamides into the reaction (Scheme 17).

Scheme 17
Optimal conditions for the asymmetric synthesis of isothiazoles

Syntheses by Ring Transformations
Formally, reactions for the synthesis of substituted isothiazoles on the basis of other heterocycles can be considered within the framework of the three previous approaches, since they usually proceed through the stage of breaking the bonds in the initial cyclic molecule and subsequent heterocyclization of the resulting intermediate. However, in our opinion, it is advisable to single out the reactions that result in the transformation of other heterocycles into isothiazoles as a separate approach. This is due, first of all, to the rather complicated mechanism of such reactions, and to a certain non-obviousness in choosing possible synthetic equivalents when analyzing the structures of the desired isothiazoles.

Review Syn thesis
An important example of this approach is the synthesis of isothiazoles based on N-substituted 3-isothiazolones. 3-Isothiazolones 36a-i can be transformed into functionalized 3-aminoisothiazoles 37a-i by sequential treatment with phosphoryl chloride and ammonia (Scheme 18). 62 Among the methods for the synthesis of isothiazoles based on other heterocycles, the recently proposed method for the synthesis of 3-phenyl(heteroaryl)isothiazole-3-carboxylic acid ethyl esters 38a-d via the tandem photoarylation and photoisomerization of 2-iodothiazole-5-carboxylic acid ethyl ester 39 is of considerable interest (Scheme 19). 63 It should be noted that no rearrangement occurred in the case of a similar 2-chloro-substituted thiazole.
Recently, an original method for the synthesis of 3,4,5functionalized isothiazoles 40 was developed through rhodium-catalyzed transannulation of 1,2,3-thiadiazoles 41 64 with alkyl, aryl, and hetaryl nitriles 42 through the formation of a rhodium -thiavinyl carbenoid. The authors suggest that in the reaction with nitriles, the -thiavinyl carbenoid acts as an equivalent of a 1,3-dipole with reversed polarity (Scheme 20).
Later, this method was successfully used by the same authors to synthesize a series of bi-, tri-, and tetracyclic isothiazoles 43 with good to excellent yields through the intramolecular transannulation of cyanothiadiazoles 44 (Scheme 21). 65 Isothiazoles can be obtained on the basis of 1,2,3-dithiazoles. Recently, improved conditions for the ring transformation of 1,2,3-dithiazoles 45 into isothiazole-5-carbonitriles 46 were reported (Scheme 22). 66 Shorter reaction times correlated with higher isothiazole yields and the use of THF as solvent in almost all cases.

Scheme 22
Preparation of 5-cyanoisothiazoles through the acidcatalyzed RORC reaction

Isothiazoles by Ring Functionalization Reactions: Nucleophilic Substitution, Cross-Coupling and Side-Chain Functionalization
Next, we will consider some methods for the synthesis of isothiazoles in which reagents containing the formed isothiazole ring are involved. The chemical properties of isothiazoles are largely defined by the presence of the delocalized -orbitals system. Isothiazoles have a high degree of aromaticity in accordance with the HOMA (harmonic oscillator model of aromaticity) criterion. In this respect, among the 1,2-azoles, isothiazoles occupy an intermediate position between isoxazole and pyrazole, being much more aromatic than isoxazoles, but less so than pyrazoles. Isothiazole derivatives are also more aromatic than thiazole derivatives. Positions 3 and 5 of the isothiazole ring are favorable for the attack of nucleophilic reagents, while position 4 is Scheme 18 Preparation of 3-aminoisothiazoles on the base of 3-isothiazolones

Review Syn thesis
preferential for the attack of electrophilic agents. It should be noted that position 5 of the isothiazole ring is more active in nucleophilic substitution reactions than position 3. In some cases, interactions with nucleophilic and electrophilic reagents may lead to the ring-opening of the isothiazole. 33 The achievements in the development of methods for the functionalization of the isothiazole nucleus and advances in the transformation of the side chains of the heterocycle, without involving the heterocycle itself in the reaction, will be considered separately. Significant attention will be paid to the development of the chemistry of halogen-substituted isothiazoles, which are highly reactive synthetic blocks, allowing the ability to obtain polyfunctional isothiazoles with a wide variety of substituents.
Fairly recently, the possibility of direct oxidative alkenylation of the isothiazole heterocycle at the unsubstituted position 4 was investigated, and it was found that the reactions proceeded with low yields. This was demonstrated by the example of the reaction of 3-methyl-5-phenylisothiazole (47) with n-butyl acrylate (48). 67 In addition, along with product 49, 52% of the initial isothiazole 47 was recovered from the reaction mixture (Scheme 23).

Scheme 23 Oxidative alkenylation of the isothiazole ring
It should be noted that the introduction of isoxazole, an isothiazole heteroanalogue, to the reaction under the same conditions led to the formation of the target alkenyl isoxazoles, with yields of 50-68%.
Because of this, the Heck reaction using haloisothiazoles remains the preferred method of alkenylation of the isothiazole heterocycle, despite the moderate yields of the corresponding alkenyl isothiazoles and the formation of a noticeable amount of by-product. 68 In recent years, considerable attention has been paid to metalation reactions of the isothiazole core for the subsequent preparation of reactive isothiazole blocks for cross-coupling reactions. Advances in this field of isothiazole chemistry have been discussed in detail by Nutaitis. 69 A mild approach to synthesize 3-amino-substituted isothiazole sulfoxides 50 through oxidation of the corresponding 3-aminoisothiazoles 51 with arylsulfonyloxaziridines 52 has been reported (Scheme 24). 70 Only minor amounts of dioxides 53 were formed under the described conditions. The reactivity of the resulting isothiazole sulfoxides toward sulfur nucleophiles has been studied and resulted in the formation of 5-sulfanyl-substituted 4,5-dihydroisothiazoles.
In 2019, the same group developed an advanced approach for the synthesis of chiral 3-amino-substituted isothiazole sulfoxides by utilizing (+)-and (-)-[(8,8-dichlorocamphoryl)sulfonyl]oxaziridine under microwave irradiation. 71 Relatively little work in the literature is devoted to the transformations of chlorine-substituted isothiazoles; however, these compounds enter into similar reactions to their bromine and iodine analogues, but often under more severe conditions and react at slower rates.

Scheme 25 Selective arylation of 3,5-dichloro-4-cyanoisothiazole
In some cases when using chlorine derivatives of isothiazoles, it is possible to synthesize the target compounds with yields greater than those obtained when using bromo derivatives.
Thus, it was found that 3-bromo(chloro)isothiazole-4carbonitriles 56a and 56b allow direct arylation at position 5 of the heterocycle in the presence of silver fluoride to give the corresponding 5-phenylisothiazoles 57a and 57b (Scheme 26). 73 Conditions for the preparative synthesis of diisothiazole derivatives 58a and 58b were also developed. Chlorine derivatives of isothiazole were formed in high yields, both in the case of arylation and in the synthesis of diisothiazole derivatives.

Review Syn thesis
was only formed in small amounts (Scheme 27). 74 By varying the temperature and duration of the reaction, the maximum yield of isothiazole 61 reached 11%.
The chemistry of chlorine-substituted isothiazoles was developed in the Laboratory for Organoelement Compounds of the Institute of Physical Organic Chemistry at the National Academy of Sciences of Belarus. In the course of the research conducted at the laboratory, it was shown that isothiazoles containing chlorine atoms at positions 4 and 5 of the heterocycle and an electron-withdrawing group at position 3, successfully enter into a nucleophilic substitution reaction. When this occurs, the chlorine atom at position 5 of the heterocycle is replaced, while position 4 remains unaffected. Research on the transformation pathways of perchloroisothiazoles was initiated with 4,5dichloro-3-trichloromethylisothiazole, on the basis of which many previously undescribed substituted 4chloroisothiazoles were synthesized.

Scheme 32 Nucleophilic substitution in 4,5-dichloroisothiazole-3carboxylic acid
Subsequently, 4,5-dichloroisothiazole-3-carboxylic acid tert-butyl ester 76, obtained from acid chloride 77, was used to study the possibility of carrying out reactions with N-nucleophiles (Scheme 33). The possibility of promoting the nucleophilic substitution of the chlorine atom at the 5position of the heterocycle with amines in the presence of fluorine ions was demonstrated. 78 The yield of the corresponding 5-aminoisothiazoles 78 varied depending on the solvent selected, on the presence of fluoride ions in the reaction mixture, on the temperature, and on the nature of the amine added to the reaction.
The reactivity of amines in the nucleophilic substitution of the chlorine atom at position 5 decreases in the series shown in Figure 1.

Review Syn thesis
Reactions with O-, N-and S-nucleophiles were investigated using ketone 81b. The reactions of this ketone with O-nucleophiles -sodium alkoxides -in a medium of the corresponding alcohol at 60 °C resulted in alkoxy derivatives 82a and 82b, while reactions with S-nucleophilessodium thiolates, generated in situ in anhydrous methanol, led to the corresponding sulfides 83a and 83b. The reaction with piperidine, as an example of an N-nucleophile, was carried out in ethanol with a double excess of piperidine, and the yield of the corresponding 5-piperidinyl derivative 84 was 85% (Scheme 35).
Some of the synthesized isothiazole-containing amides, esters, and ketones were able to exhibit potentiating activity in compositions with the insecticides imidacloprid and/or -cypermethrin, with larvae of the Colorado potato beetle. [84][85][86][87] Some derivatives with fungicidal activity were also found. 88 In the case of -cypermethrin, when used in a composition with an insecticide, the maximum synergistic effect was achieved by using a 4,5-dichloroisothiazole derivative with 5-10% of the active component of the insecticidal composition. 89 Based on 4,5-dichloroisothiazole-3-carboxylic acid amide (85) and azide 86, both obtained from 4,5-dichloroisothiazole-3-carboxylic acid chloride (77), 3-amino-4,5-dichloroisothiazole (87) was synthesized by the Hoffmann and Curtius reactions. 90 It was possible to achieve a 92% amine yield via the preliminary in situ preparation of ethyl carbamate 88, which was then subjected to alkaline hydrolysis (Scheme 36). 4,5-Dichloroisothiazole-3-carboxylic acid nitrile (89) was synthesized by the action of phosphorus pentoxide on 4,5-dichloroisothiazole-3-carboxylic acid amide (85), both without solvent and in tetrachlorethylene. In both cases, the target nitrile was obtained in a quantitative yield. 91 Subsequently, reactions of the synthesized nitrile with O-, Nand S-nucleophiles were studied (Scheme 37).
The reaction with O-nucleophilic sodium methoxide led to the formation of a mixture of 5-methoxy-4-chloro-3-cyanoisothiazole (90a) and the product of its alcoholysis 90b, whilst the reaction with piperidine in methanol led to the formation of 5-piperidinyl-substituted isothiazole 91. Reactions with thiolates using benzylmercaptan and thiophenol as thiols proceeded in methanol with satisfactory yields, with the formation of derivatives 92a and 92b, respectively. When n-butylmercaptan was used, a mixture of the thiobutyl derivative 93a and the product of its alcoholysis 93b was formed. In isopropyl alcohol, the yield of isothiazole 93a was 68%.
The possibility of further transformation of the nitrile group was illustrated by synthesizing disubstituted 1,2,4oxadiazoles 94 after obtaining the 4,5-dichloroisothiazole-3-carboxylic acid amidoxime 95, and its subsequent acylation and cyclization (Scheme 38). 92 The yields of acylamidoximes 96 were 85-95% for all derivatives, except for the case when the acylation was carried out with trichlorovinylacetic acid, for which the yield of the corresponding acylamidoxime was 71%. Method B provided slightly higher yields of the target acylamidoximes compared with method A. The acylamidoximes were further cyclized in the presence of acetic acid at reflux in yields of

Review
Syn thesis [90][91][92]. In the case of pivaloylamidoxime, the heterocyclization did not proceed under the proposed conditions, presumably due to steric hindrance.
Nitrile 89 was successfully used as a starting material for the synthesis of isothiazole-containing alkyl ketones 97a and 97b by addition reactions with alkylmagnesium halides (Scheme 39). 93

Scheme 40 Some transformations of 3-acetyl-4,5-dichloroisothiazole
First, reactions with amines were investigated. It had been previously shown that the reaction of (4,5-dichloroisothiazol-3-yl) phenyl ketone with amines proceeded with substitution of the chlorine atom at position 5 of the heterocycle by the amine residue. In aprotic bipolar solvents (N-methylpyrrolidone and DMSO) at 130-140 °C, the process was complete in 6 hours. 94 Compared to (4,5-dichloroisothiazol-3-yl)(4-methylphenyl) ketone, the reactions of ketone 97b with amines (morpholine and piperi-dine) were more active. In a DMSO solution at 70 °C, nucleophilic substitution of the chlorine atom at position 5 of the heterocycle was complete within 5 hours, with good yields being obtained. The ketones 97b and 98a were further reduced to secondary alcohols 99a and 99b by the action of sodium borohydride in isopropanol (Scheme 40).
In addition, the reactions of (4,5-dichloroisothiazol-3yl) methyl ketone (97b) with elemental bromine in carbon tetrachloride and anhydrous acetic acid were studied (Scheme 41). Bromination in these two solvents proceeded with significant tar formation, leading to bromomethyl(4,5dichloroisothiazol-3-yl) ketone 100 in yields of 32% and 46%, respectively. Substitution of two hydrogen atoms in the methyl group for bromine atoms was not observed. The reaction in carbon tetrachloride was complete in 2 hours, whilst the bromination in acetic acid was complete in 1 hour. It was noted that replacement of the solvent with chloroform or dichloromethane did not lead to positive results; in both cases, the bromination did not proceed. The reaction of bromoketone 100 with thiourea in an ethanol solution at 60 °C proceeded smoothly over 3 hours and resulted in 2-amino-4-(4,5-dichloroisothiazol-3-yl)thiazole (101) in a yield of 82%.

Selected Synthesis of Biologically Active Isothiazole Derivatives
As already mentioned, compounds containing an isothiazole fragment have a broad spectrum of biological activity, including pesticidal, anticancer, antimicrobial, and antiviral. The mechanism of the biological action of these compounds has only been studied for some of their representatives.
For example, compound 115 ( Figure 2) is a vascular endothelium growth factor receptor inhibitor (VEGFR-2) of tyrosine kinase, and it has been proposed as an anticancer therapy drug that prevents the growth and metastasis of tumors. 97 Although being an inhibitor of a protein significant for the treatment of cancer diseases, a reinforcing effect was not observed during clinical trials in combination with known antitumor drugs. 98 Isothiazole-modified nucleoside 116 (Figure 2) is effective against the first type of herpes virus (HSV-1), and the interaction mechanism involves its binding to thymidine kinase HSV-1. 99

Figure 2
Examples of biologically active isothiazoles for which the mechanism of biological activity has been proposed Recently, it has been shown that the isothiazole nuclei of a number of derivatives can interact with target biomolecules, not only through van der Waals interactions and hydrogen bonds, 100,101 but also by covalent binding at the unsubstituted position 4 of the heterocycle as a result of bioactivation. 102 This is an important factor that must be considered when designing and synthesizing new biologically active compounds containing an isothiazole heterocycle.

Review Syn thesis
The available literature data on the synthesis of biologically active isothiazoles includes not only information about the relationships between the structures of compounds and their biological activities, but also important information on the approaches used in multistep targeted syntheses of isothiazole-containing molecules. Considering the target functionalization of isothiazoles, it seems appropriate to pay attention not only to individual methods of isothiazole heterocycle formation and ways of modification, but also to synthetic strategies and approaches used in multistage syntheses of target isothiazoles. As examples of such strategies and approaches, the synthetic schemes toward some biologically active isothiazoles appear particularly useful and informative. At the same time, attention will be paid to the stages that include the formation or involvement of the isothiazole heterocycle in chemical transformations.
We can identify three rather conventional strategies for the targeted production of biologically active isothiazoles: (1) Introduction of the isothiazole fragment at the final stage.
As an example of the first strategy, we can cite the final stages of the synthesis of nucleoside 116 (Scheme 46). 99 3′,5′-Di-O-acetyl-2-deoxy-5-iodouridine 117 was introduced into the Sonogashira reaction with 3,3-diethoxyprop-1-yne (118) and subsequent hydrolysis of the obtained alkyne derivative 119 gave aldehyde 120. This in turn was reacted with sodium thiosulfate and the resulting thiosulfate derivative 121 was treated with liquid ammonia without purification to give nucleoside 116.

Scheme 46 Synthesis of a nucleoside bearing an isothiazole ring
In this example, the formation of the isothiazole ring is a factor limiting the yield of the target nucleoside 116. However, low yields of the target products can be justified during initial research and bio-testing, and if necessary (for example, when the desired biological activity is detected), further optimization of the procedure can be carried out.
Another example of this strategy is the formation of substituted isothiazoles via the transformation of other functionalized heterocycles such as isoxazoles. Thus, in the synthesis of cyclooxygenase inhibitor 1 (COX-1) analogues, isothiazole derivative 122 was obtained starting from isoxazole inhibitor 123 through reductive opening of the isoxazole ring with hydrogen in the presence of Raney nickel, followed by cyclization of the resulting enamine ketone 124 by the action of phosphorus pentasulfide in the presence of chloranil (Scheme 47). 103 This method has several disadvantages; however, the yield of the corresponding enamine ketones (38-90%) strongly depends on the substituents present on the isoxazole ring, and their cyclization into isothiazoles usually proceeds with rather low yields (21-51%). 104 Regardless, this pathway can be useful in the synthesis of promising biologically active compound libraries for biological screening, subject to the availability of the corresponding substitute isoxazoles.
The strategy associated with the convergent synthesis of isothiazoles, including demonstrating the potential of isothiazole halogen derivatives in preparative organic synthesis, was used in the final stage of the preparation of a selective inhibitor of the metabotropic glutamate receptor 5 (mGluR5) 125 (Scheme 48). 105,106 3,4-Dibromisothiazole amide 126 was introduced into a Suzuki cross-coupling reaction with boric acid pinacol ester 127. The product 128 thus obtained was then subjected to a Stille reaction with the pyridine organotin derivative 129 to deliver the target product 125.

Review Syn thesis
An alternative method for the synthesis of the desired isothiazol-3-yl-oxadiazoles consisted of the initial reductive alkylation of compound 132, transformation of the amide groups of the resulting compounds 134 into hydrazide groups, subsequent formation of semicarbazides, and then formation of the 1,3,4-oxadiazole fragments.
A series of vanillin-containing isothiazole derivatives was synthesized by successive transformations of the substituents on the isothiazole nucleus. It has previously been shown that 4,5-dichloroisothiazole-3-carboxylic acid vanillin ester exhibits potentiating activity in a composition with the pyrethroid insecticide cypermethrin, and its azomethine and amine derivatives possess potentiating activity when combined with the neonicotinoid insecticide imidacloprid. 85,108 The effect was observed when testing the corresponding insecticidal compositions on Colorado potato beetle larvae. In order to clarify the effect of structural and functional changes in the molecules of the vanillin isothiazole derivatives on their biological activity, an isovanillin analogue of the isothiazole vanillinate was synthesized, as well as 5-alkyl(aryl)thio-substituted 4-chloroisothiazoles containing the vanillin moiety (Scheme 50). 109 An optimized method was used for producing 5-butyl(benzyl, phenyl)thio-4-chloroisothiazole-3-carboxylic acids 75a-c. The methyl ester of 4,5-dichloroisothiazole-3-carboxylic acid 135 was treated in situ with the corresponding sodium thiolates in anhydrous methanol, followed by hydrolysis of the intermediate methyl-5-alkyl(benzyl, phenyl)thio-4chloroisothiazole-3-carboxylates 136. The synthesis of vanillin esters 137a-c was carried out by the acylation of vanillin with 5-butyl (benzyl, phenyl)thio-4-chloroisothiazole-3-carbonyl chlorides 138a-c, which were obtained by boiling the acids 75a-c with thionyl chloride in the presence of a catalytic amount of DMF.

Review Syn thesis
Azomethines 139a-c were obtained by condensation of esters 137a-c with p-toluidine in dry methanol, with yields of 78-92%. Compounds 139a-c were further reduced to the corresponding amines 140a-c with high yields by the action of sodium borohydride and acetic acid in benzene.
Vanillin ether 141, containing a 4,5-dichloroisothiazole moiety, and also azomethine 142 based on it, were prepared in order to study the effect of the nature of the linker between the isothiazole and vanillin fragments on the biological activity of vanillin derivatives of isothiazole (Scheme 51). 110 (4,5-Dichloroisothiazol-3-yl) carbinol 143 was reacted with thionyl chloride in carbon tetrachloride to form (4,5-dichloroisothiazol-3-yl) chloromethane 144 in a satisfactory yield. Alkylation of vanillin with chloromethane 144 in dimethylformamide using sodium hydride as the base led to the formation of vanillin ether 141 in a 71% yield. The resulting ether was introduced into a condensation reaction with p-toluidine in methanol in the presence of a catalytic amount of acetic acid to form azomethine 142 (Scheme 51). Isothiazolic derivatives of comenic acid were prepared in a similar manner. 111 Another example of such a strategy is the synthesis of the Aurora kinase inhibitor, serine/threonine kinase, which plays a crucial role in cell proliferation (Scheme 52). 112 Methyl ether 145 was reacted with intermediate 146 in the presence of sodium hydride, and the carboxyl group in the obtained product 147 was reduced by lithium triethylborohydride in tetrahydrofuran. The resulting alcohol 148 was then mesitylated to form ester 149. Transformation of the ester group into a tertiary amino group by reaction with 2-(ethylamino)-2-methylpropan-1-ol led to the formation of compound 150. After deprotection of the pyrazole nitrogen by the action of hydrochloric acid in dioxane, the desired inhibitor 151 was obtained.

Review Syn thesis
ylic acid hydrazide (153). Treatment of hydrazide 153 with nitrous acid (a mixture of NaNO 2 and HCl) resulted in the target 5-benzylthio-4-chloroisothiazole-3-carboxylic acid azide (152). However, due to the low solubility of hydrazide 153 under the reaction conditions, the process proceeded slowly and the yield of azide 153 did not exceed 65%, whereas the reaction of 5-benzylthio-4-chloroisothiazolecarbonyl chloride (138b) and NaN 3 gave the target azide 152 in a yield of 82% (Scheme 53).
The hydrazide 153 was synthesized in a 95% yield by the action of hydrazine hydrate on ester 136b in methanol. Subsequently, azides 86 and 152 were used to synthesize carbamates, as immediate precursors of ureas (Scheme 54).
The synthesized isothiazolylcarbamates 154a and 154b were further reacted with aliphatic amines, including functionalized examples (n-hexylamine, 6-aminohexanol, 2aminoethoxyethanol, N′,N′-dimethylpropan-1,3-diamine). In addition to the p-fluorophenol carbamate, ethyl carbamate 155 was obtained from azide 152; it had greater solubility but did not react with amines under the utilized conditions, even with prolonged boiling of the reaction mixture. In the case of -aminobutyric and -aminocaproic acids, which are poorly soluble in chloroform, the reactions with urethanes 154a and 154b were carried out in aqueous ethanol. 115 The obtained carbamides 156 were then transformed into the corresponding salt forms 157 by treatment with sodium carbonate (Scheme 55).
The amide synthesis involved the acylation of selected amino acids with 4,5-dichloroisothiazole-3-carboxylic acid azide 86 in methanol, followed by conversion of the synthesized amides 158 into their salt forms 159 by reaction with sodium bicarbonate (Scheme 56).
Among biologically active isothiazoles, benz[d]isothiazoles occupy an important place. The benz[d]isothiazole moiety has been successfully used in the design and synthesis of neuroleptic ziprasidone as well as in the synthesis of a number of ureas and thioureas, which showed both in vitro antiglycosylation activity and the ability to inhibit urease. 116 Some ureas and thioureas containing benzo[d]isothiazole fragments show high inhibitory activity against Mycobacterium tuberculosis GyrB DNA gyrase. 117 In this regard, it is necessary to mention the recently proposed original approach to the synthesis of substituted benz[d]isothiazoles based on the Diels-Alder reaction, which has been successfully demonstrated with the example of 3-phenyl-4,5-bis(carbomethoxy)isothiazole (160) as the starting compound (Scheme 57). 118 The carboxyl groups of isothiazole 160 were transformed into carbinols by the action of borohydride in an ethanol/tetrahydrofuran medium, forming the diol 161. The carbinol groups of diol 161 were further converted into bromomethyls by reaction with phosphorus tribromide and pyridine in dichloromethane. The reaction of the

Review Syn thesis
resulting 4,5-bis(bromomethyl)-3-phenylisothiazole (162) with sodium iodide in dimethylformamide led to the generation of the highly active diene 163, which was immediately reacted with dimethyl acetylenedicarboxylate (DMAD). The resulting adduct 164 was oxidized with atmospheric oxygen to form the benz[d]isothiazole derivative 165. The proposed approach provides access to quite a wide range of substituted benz[d]isothiazoles, and is expected to find future applications in the synthesis of many biologically active derivatives of benz[d]isothiazole.
As an example of other methods for condensed isothiazole derivatives, we should cite the synthesis of the fungicide phytoalexin brassilexin along with its analogues 166, which also exhibit antifungal activity and contain the isothiazole cycle. One of the proposed strategies for the synthesis of these compounds is the Vilsmeier formylation of substituted indolin-2-thiones 167, followed by treatment with aqueous ammonia and oxidation of the extracted imines 168 with iodine in pyridine (Scheme 58). 119

Scheme 58 Synthesis of brassilexin and its analogues
The formation of by-products 169 was observed during the formylation stage of the reaction, and so the imines 168 together with impurities were introduced into the oxidation reaction with iodine, and the impurities were removed during purification of the target products 166.
An alternative strategy was proposed for the synthesis of brassilexin (166a) through the formylation of indolin-2one (170), followed by heterocyclization of the resulting 2bromo-1H-indole-3-carbaldehyde (171) in a reaction with urea and sodium thiocyanate under microwave irradiation (Scheme 59). 120 This strategy has also been successfully applied in the synthesis of isothiazole-containing steroids. 120

Scheme 59 An alternative way for the synthesis of fungicide brassilexin
Isothiazoles condensed with pyrazole rings were found to be promising biologically active compounds with fungicidal properties. 121,122 For their synthesis, a strategy has been reported consisting of the oxidation of 1-aryl-5-amino-3-methylpyrazole-4-carboxylic acid thioamides 172 with hydrogen peroxide in pyridine, leading to good yields of the desired 3-aminopyrazolo [3,4-c]isothiazoles 173 (Scheme 60). In this case, nitrile 174 was formed in trace amounts. At the same time, the use of iodine as an oxidizing agent in a tetrahydrofuran medium resulted in the formation of either only product 174 or a mixture of products with a predominance of the 4-cyano derivative 174 in a ratio of 95:5. In the case of a 2,5-dichlorophenyl derivative, the corresponding nitrile was the main oxidation product. Some of these synthesized 5-aminopyrazolo [3,4-

Scheme 61 Investigation of the reaction between 5-aminopyrazoles and Appel's salt
The yields of compounds 177 and 178 depend on the temperature, reaction time, acidity of the reaction mixture, and substituents on the pyrazole ring. When substituted 1H-pyrazoles were introduced into the reaction, the main products were pyrazole derivatives of 1,2,3-dithiazole, regardless of the reaction conditions, and pyrazolo [3,4-d]isothiazole-3-carbonitriles did not form. This is particularly interesting because from the corresponding pyrazole derivatives of 1,2,3-dithiazole, it is possible to synthesize thiazoles isomeric to isothiazoles 177 by thermolysis, which may be convenient in the process of synthesizing libraries of compounds for biological screening.

Isothiazoles in the Synthesis of Transition-Metal Complexes and in Metal-Complex Catalysis
The properties manifested by metal complexes are largely determined by the ligand environment of the metal, which ensures the creation of a specific distribution of the electron density on the metal atom and the formation of a spatial framework around it. Information about the metal complexes of the isothiazole series is sparse and fragmentary, and techniques for their practical application have been studied only as isolated examples.
The first information regarding such metal complexes, published in two articles in 1971, was devoted to the synthesis and study of the structure of Co(II), Ni(II), Cu(II) and Pt(II) complexes with unsubstituted isothiazole as a ligand. 126,127 For cobalt, complexes CoX 2 L 2 , CoX 2 L 4 and [CoL 6 ](ClO 4 ) 2 were obtained, where L is an unsubstituted isothiazole and X = Cl, Br, I. 126 The characterizations of their structures was accomplished by using elemental analysis, diffuse reflectance spectroscopy, magnetic susceptibility, conductivity in solution, and IR spectroscopy. CoCl 2 L 2 and CoBr 2 L 2 complex-es are polymer structures, CoCl 2 L 4 and CoBr 2 L 4 are octahedral, and CoI 2 L 2 and CoI 4 L 2 are tetrahedral, but in solution all complexes are characterized by a tetrahedral structure. For the CoI 4 L 2 complex, instability with regard to the action of atmospheric oxygen and decomposition in nitromethane solution with the formation of molecular iodine and the CoI 2 L 2 complex were observed. The [CoL 6 ](ClO 4 ) 2 complex is assigned an octahedral structure, both in solid form and in nitromethane solution, with the perchlorate anion in the outer sphere of the complex. Based on the electronic and IR spectra, it was suggested that isothiazole is coordinated through a nitrogen atom. 126 In the other paper published in 1971, 127 the trans-Co(NCS) 2 L 4 complex was obtained, to which the octahedral structure was also attributed as a result of magnetic susceptibility data. The hypothesis of the trans-form of the complex is suggested based on the reaction with ,′-dipyridyl, leading to the formation of a Co(NCS) 2 (bipy) 2 complex as a result of ligand exchange. The same paper describes the synthesis of complexes CuCl 2 L 2 , CuBr 2 L 2 , Cu(NO 3 ) 2 L 2 , [LH + ] 2 [CuOCH 2 CH 3 (NO 3 ) 3 L 2 ] (unstable), Cu(NO 3 ) 2 L 4 , NiCl 2 L 4 , NiBr 2 L 2 , Ni(ClO 4 ) 2 L 6 , and cis-PtCl 2 L 2 . The synthesized complexes were characterized using IR spectroscopy, elemental analysis, magnetic susceptibility, and powder X-ray diffraction. For complexes of the MHal 2 L 2 type [M = Cu(II), Co(II); Hal = Cl, Br] and for NiBr 2 L 2 , a polymer octahedral structure with bridging halogen atoms and isothiazole in the trans position was proposed, while complexes NiCl 2 L 4 , Cu(NO 3 ) 2 L 4 , Cu(NO 3 ) 2 L 2 , and Ni(ClO 4 ) 2 L 6 were characterized as octahedral. For cis-PtCl 2 L 2, a cis-planar configuration was proposed with coordination through the nitrogen atom of the cycle. Later, various cobalt and nickel complexes with 3-, 4-and 5-methylisothiazoles were studied in detail. 128,129 It was also shown that 3-methylisothiazole was only able to form tetrahedral complexes of the MeX 2 L 2 type, which was associated with steric hindrance created by the methyl group at position 3 of the heterocycle. The isothiazole nuclei in all the synthesized complexes are coordinated through a nitrogen atom.
The literature describes only one example of an isothiazole-containing complex with PdCl 2 , the structure of which was accurately determined by X-ray crystal structure

Review
Syn thesis analysis (Figure 3). 131 In this complex, palladium had a planar environment with trans-oriented benzo[d]isothiazole ligands.
As part of studying the ability of 1,2-azoles to form metal complexes, stability studies of isothiazole complexes with cobalt(II), nickel(II), copper(II), zinc(II), and silver(I) were carried out by potentiometric and photocolorimetric methods. 132 The stability of the complexes varies in the series of 1,2-azoles as follows: pyrazole > isothiazole > isoxazole. It was suggested that the higher stability of the isothiazole complexes in comparison with their isoxazole analogues could be explained by the possibility of additional bond formation between the isothiazole and the metal cation due to the presence of an unoccupied d-orbital on the sulfur atom in the heterocycle.
The literature describes bimetallic tetraselenocyanate complexes of cobalt(II), nickel(II), cadmium(II), and mercury(II), in which isothiazole, 4-methylisothiazole, and 4-benzylisothiazole act as ligands. 133,134 Assumptions about the structures of these complexes were made based on elemental analysis, UV-VIS and IR spectroscopy, magnetic susceptibility, and the HSAB theory, wherein a single monomer complex L 2 Ni(NCSe) 2 Hg(NCSe) 2 (L= methylisothiazole, with selenocyanate acting as a bridging ligand) was separated, in which nickel was in an octahedral environment, probably due to the axial coordination of the selenocyanate fragments of the upper layers. All other bimetallic complexes of different composition are described as polymeric tetrahedral, where the selenocyanate acts as a bridging ligand, the N-terminus is coordinated on cobalt and nickel, and the Seterminus is coordinated on cadmium and mercury. Coordination of isothiazoles occurs in these cases via a nitrogen atom at the axial positions in the case of Ni(II) and Co(II), or through sulfur in the case of Cd(II) and Hg(II).
Data on isothiazole-containing carbonyl complexes of tungsten L x W(CO) 6-x, molybdenum LMo(CO 5 ), and chromium L x Cr(CO) 6-x (L is the isothiazole ligand; x = 1, 2), obtained by ligand exchange from the hexacarbonyl of the corresponding metal and isothiazole, 4-methylisothiazole or 5-methylisothiazole under ultraviolet irradiation, have been published. 135,136 At the same time, depending on the irradiation time of the reaction mixture, substitution of one to two carbonyl fragments in the starting metal hexacarbonyl has been observed. Based on IR spectra, it has been established that the synthesized complexes have a C4 v symmetry group, and based on mass spectrometric data for the fragmentation of L x W(CO) 6-x and L x Cr(CO) 6-x complexes and the starting isothiazole ligands, it has been found that in all cases, the coordination was achieved through the nitrogen atom. 136 This was also consistent with the 1 H NMR data for the synthesized complexes. An attempt was made to synthesize the isothiazole -complex based on the triacetonitrile tricarbonyl complex of chromium [(CH 3 CN) 3 Cr(CO) 3 ], but an unstable product was separated with an L 3 Cr(CO) 3 (L = isothiazole) structure, according to IR spectroscopy data. 136 Finally, some examples of isothiazole complexes, in which the metal is coordinated not only through ring heteroatoms, but also through heteroatoms of exocyclic groups, are known. Thus, diperchlorate isothiazole complex 179 was obtained by treatment of Δ-bis(ethylenediamine)threoninatocobalt(III) trifluoromethansulfonate 180 with thionyl chloride in dimethylformamide, followed by ion exchange chromatography. In this case, the isothiazole-3-carboxylic acid acts as a bidentate ligand, chelating cobalt through the heterocyclic nitrogen atom and carboxyl group (Scheme 62). 137

Scheme 62 Formation of the isothiazole ring in cobalt chelate
The structure of the complex was confirmed by X-ray crystal structure analysis. Threonine serves as the starting material for the formation of the isothiazole ring. In this case, thionyl chloride acts as both a dehydrating agent and a sulfur atom donor for the isothiazole heterocycle. It is assumed that in the first stage of this reaction, cobalt-chelating threonine chloride is formed, with a sufficiently acidic proton on the -carbon atom, which makes it possible to proceed with subsequent transformations.

Scheme 64 Preparation of 3-substituted isothiazoles from 3,5-dimethylisothiazole
Based on the synthesized isothiazoles, binuclear isothiazole-containing silver triflate complexes [LAgOSO 2 CF 3 ] 2 (L = 181a, 181b, 183) and [LAg] 2 [O 3 SCF 3 ] 2 (L = 186) were obtained. The structures of the complexes were established by X-ray crystal structure analysis in all cases, except for the complex with ligand 181a. In the case of L = 183, 186, ligands were coordinated to the silver atom by the nitrogen atom of the heterocycle and exocyclic heteroatoms (nitrogen or sulfur). In the case of L = 181b, the silver coordination occurs exclusively on the exocyclic heteroatoms (through the nitrogen of the azomethine and pyridine fragments).
Metal complexes with Cu(II) were obtained based on 4,5-dichloroisothiazole-3-carboxylic acid, its amide, and benzotriazolamide. 27,139,140 Polymer complexes of copper [LCuCl 2 ] n , LCuBr 2 (L = 4,5-dichloroisothiazole-3-carboxylic acid amide), Cu(L)(BtaH)(H 2 O) 2 (NO 3 ) (L = 4,5-dichloroisothiazole-3-carboxylic acid, BtaH = benzotriazole), and (L)(CuH 2 O)Cl·0.5H 2 O (L = 4,5-dichloroisothiazole-3-carboxylate) were synthesized. The complexes were characterized by X-ray crystal structure analysis. In these complexes, isothiazole ligands chelated a copper atom with a nitrogen atom of the heterocycle and with an oxygen atom of an amide or carboxyl group. The complex [Cu(L 2 )Cl 2 ] n possesses fungicidal properties against the phytopathogenic fungi Botrytis cinerea and Fusarium sp., completely inhibiting the development of the fungi at a concentration of 0.125%, according to biological tests. The Cu(L 2 )Br 2 complex, being added at a 5% amount relative to the neonicotinoid insecticide imidacloprid, increases by almost 2 times the toxicity of the insecticide toward Colorado potato beetle larvae, which increases the effectiveness of the insecticide and reduces its consumption. 139 Complexes of 4,5-dichloroisothiazole-3-carboxylic acid ethanolamide with copper bromide and copper chloride were also obtained, and according to XRD data, 4,5-dichloroisothiazol-N-(2-hydroxyethyl)-3carboxamide was coordinated to copper(II) in a tridentate manner. In the bidentate cyclic-type complex, it is coordinated on the nitrogen atom of the heterocycle and on the exocyclic oxygen atom of the amide group with the formation of the five-membered metallocycle CuNCO, and also on the oxygen atom of the substituent hydroxy group, and all these bonds form polymer chains. The complex of 4,5-dichloroisothiazole-N-(2-hydroxyethyl)-3-carboxamide with copper(II) bromide ( Figure 4) can enhance the action of the insecticides cypermethrin and imidacloprid, and at the same time, copper bromide and the ligand separately did not show any similar activity with insecticides. 141

Figure 4
The structure of a polymeric copper complex of 4,5-dichloroisothiazole-N-(2-hydroxyethyl)-3-carboxamide with copper(II) bromide (reproduced with permission). 141 The structure of the polymer complex with copper chloride is similar.
In 2011, the Pd(II) complex of composition L 2 Pd (L = 4,5dichloroisothiazole-carboxylate) was synthesized from 4,5dichloroisothiazole-3-carboxylic acid. 26 It could not be obtained in crystalline form, and therefore, to describe its structure, quantum chemical modeling using the B3LYP1/MIDI(3d) level of theory was used. According to the quantum chemical calculations, a flat-square structure was attributed to the complex; however, it was not possible to establish exactly whether the isothiazole fragments in the complex were in cisor trans-form due to the proximity of their calculated formation enthalpies. The complex showed catalytic activity in the Suzuki reaction: on addition of 0.1

Review Syn thesis
mol% of the complex, the reaction of 2,4-difluorophenylboronic acid with 5-bromosalicylic acid, carried out in water exposed to air at 100 °С, was complete in 15 minutes with a quantitative yield of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid being obtained. The latter is active pharmaceutical substance diflunisal, a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic effects.
The possibility of using isothiazole complexes with palladium(II) as a catalyst for cross-coupling reactions is of particular interest because of its relevance both in practical and scientific terms. Cross-coupling reactions catalyzed by palladium complexes are widely used in modern organic synthesis as a reliable method of forming carbon-carbon bonds in order to produce polyfunctional biaryls, arylated olefins, acetylenes, and their heterocyclic analogs. Compounds of this type are key structural elements of a number of modern drugs, 142 and are used to develop special purpose polymeric materials. 143 The Nobel Prize in Chemistry for 2010 was awarded for studies of cross-combination reactions, which attests to their high scientific and practical significance. 144 The key parameter determining the efficiency of a catalyst in cross-coupling reactions is the nature of the ligand on the palladium complex. Traditionally used phosphine ligands are not suitable for large-scale use due to their toxicity, their ease of oxidation, and their high cost, and therefore, the tendency over the last ten years to use heterocyclic carbenes, oxazolines, Schiff bases, and other nitrogen-containing compounds instead of phosphorus-containing ligands is quite understandable. 145 At the same time, from the point of view of ecology and large-scale practical applications of cross-coupling reactions, it would be optimal to use water as a reaction medium ('green chemistry'). [145][146][147][148] One of the most important practical examples of cross-coupling reactions is the Suzuki reaction, which involves the coupling of aryl and vinylboronic acids with aryl or vinyl halides, catalyzed by palladium complexes. The possibility of extensive adjustment of the functional environment of the chlorinated isothiazole, as well as the initial data on the successful use of the 4,5-dichloroisothiazole-3-carboxylic acid complex with palladium chloride for the Suzuki reaction in aqueous medium, indicates a high potential for further research into the design and synthesis of isothiazole ligands for palladium complexes.

Scheme 66 Model reaction -synthesis of 4′-methoxy[1,1′-biphenyl]-3carboxylic acid
As in the case of the palladium complex of acid 74, the complexes of hydrazide 187a and phenylhydrazide 187b exhibit high catalytic activity in the Suzuki reaction, albeit slightly lower than that of the 4,5-dichloroisothiazole-3carboxylic acid complex with palladium (Table 1). At the same time, the catalytic activity of the hydrazide complex was higher than that of the phenylhydrazide complex. Detailed studies on the influence of the functional environment of the isothiazole heterocycle on the catalytic activity of the corresponding palladium complexes required the creation of new ligands. For this purpose, several new derivatives were synthesized based on 4,5-dichloroisothiazole-3-carboxylic acid, which contained different substituents at position 3 of the heterocycle as well as additional coordination centers of various nature.
For this purpose, heterocyclic molecules containing 1,2,4-triazole or tetrazole rings together with an isothiazole fragment have been synthesized. 150 To construct a triazole heterocycle and to obtain (isothiazole)triazoles, an

Review Syn thesis
approach including initial synthesis of amidrazone 191 via the reaction of nitrile 89 with hydrazine hydrate was chosen (Scheme 67).
In order to obtain the target amidrazone, it was found that the reaction should be carried out with a minimal amount of methanol or without solvent at all, because otherwise the hydrazine hydrate does not react with the nitrile 89. Amidrazone 191 was further treated with acetyl chloride in the presence of triethylamine, and the resulting acyl derivative 192 was subjected to cyclization to give the target 1,2,4-triazolylisothiazole 193 by heating in glacial acetic acid followed by neutralization of the reaction mixture with KOH solution (Scheme 67). The yield of 1,2,4-triazolyl(isothiazole) 193 was 85%.
The nitrile group of carbonitriles 89 and 92b was used for the formation of tetrazole heterocycles (Scheme 68). The synthesis of tetrazolyl isothiazoles 194a,b was carried out by the reaction of sodium azide and ammonium chloride with carbonitriles 89 and 92b in methanol, with good yields being obtained.
The derivative 193 and its precursor amidrazone 191 were used for the synthesis of azole complexes. For a qualitative assessment of the mutual influence of 1,2-azole and triazole fragments in mixed ligands, palladium complexes with 1,2,4-triazole were also obtained. For the synthesized complexes, extremely low solubility was noted in organic solvents and in water, possibly due to their polymer structure, and therefore they were characterized by IR spectroscopy and elemental analysis. The model reactions presented in Scheme 66 were carried out in 50% aqueous methanol (at 20 °C and 75 °C) or in water (at 100 °C) in the presence of 0.1 mol% of palladium complexes and potassium carbonate as the base. All reactions were carried out in air in the absence of an inert atmosphere. The results of testing the catalytic activity of the complexes are presented in Table 2.
Dichloromethane was the only solvent suitable for the preparation of complexes with representatives of the synthesized ligands 195 and 197; the palladium benzonitrile complex (PhCN) 2 PdCl 2 was used as the source of palladium. The complexes were characterized by their elemental

Review Syn thesis
analyses and IR spectroscopic data. In a model Suzuki reaction between 4-methoxyphenylboronic acid (188) and 3-bromobenzoic acid (189) (Scheme 71), it was shown that palladium complexes with these ligands exhibited high catalytic activity in aqueous and aqueous-alcoholic media (Table 3).

Scheme 71
The model reaction for (isothiazol-3-yl)oxadiazoles palladium complexes catalytic activity testing As another promising group of ligands for metal complexes, N-aryl(isothiazol-3-yl)methyleneimines (aromatic azomethines) and amines were synthesized. 152,153 Conden-sation of 4,5-dichloroisothiazol-3-carbaldehyde (106) with 4-aminobiphenyl and 1-naphthylamine in methanol in the presence of glacial acetic acid resulted in 85% yields of azomethines 198a,b (Scheme 72). In the case of the 4-aminobenzoic acid ethyl ester, this technique was not useful due to only trace amounts of the target azomethine being formed. When carrying out the reaction in boiling benzene in the presence of catalytic amounts of glacial acetic acid, incomplete conversion of the starting aldehyde 106 into azomethine 198c (40%) was observed, therefore the process was carried out with higher-boiling toluene and an increased amount of acetic acid was used.
Azomethines 198a-c were further reduced to give amines 199a-c by the action of sodium borohydride and acetic acid in benzene, in 94-95% yields (Scheme 72). Reduction of the isothiazole-containing azomethine 198c proceeded only when the reaction mixture was boiled; at room temperature, there were no signs of the reaction occurring. Amine 199c was further hydrolyzed into isothiazole amino acid 200 (Scheme 73).

Scheme 73 Deprotection of carboxylic group in compound 199c
Azomethine 198b, amine 199b, and isothiazole-containing amino acid 200 (from the synthesized aromatic azomethines and amines) were used as ligands in order to obtain palladium(II) complexes by reaction with sodium tetrachloropalladate. Complexes of the composition LPdCl 2 were formed by the interaction of equimolar amounts of sodium tetrachloropalladate and the ligands in methanol at 20 °C. Since acid 200 was poorly soluble in both methanol and acetonitrile, which were previously used to produce 1,2-azole palladium complexes, the complex was synthesized in a mixture of methanol and DMF, in which derivative 200 is quite soluble. The obtained palladium complexes 198b·PdCl 2 , 199b·PdCl 2 , and 200·PdCl 2 were identified based on their elemental analyses as well as IR spectroscopic data, in which the characteristic vibration bands of the C=N and C=C bonds of the isothiazole heterocycle and the corresponding exocyclic fragments were apparent. According to their elemental analyses, they form complexes with palladium chloride with the composition LPdCl 2 . The complexes are insoluble in organic solvents and in water, which made it impossible to record their NMR spectra or to grow single crystals for X-ray crystal structure analysis. The assumption of their structure was made by analogy with the previously obtained palladium complexes with oxime ligands of the isoxazole series, 26 as well as by comparing the IR spectra of the ligands and the corresponding complexes. This indicates the participation of the heterocycle and exocyclic fragments (C=N/C-NH) in coordination with palladium. For the complex of the isothiazole amino acid 200 with palladium chloride, calculations of the geometry and IR spectrum were made at the B3LYP/6-31+G*/ LANL2TZ(f)ECP(Pd) level of theory. As a result, it was proposed that the isothiazole ligand 200 in the molecules of the complex 200·PdCl 2 is coordinated to palladium in a bidentate cyclic-type manner by the nitrogen atoms of the heterocycle and the exocyclic amino group to form a fivemembered metallocycle ( Figure 5).
Evaluation of the catalytic activity of the obtained complexes on the model reaction presented in Scheme 66 was performed under conditions similar to those used in previous tests. 149,150 The results of the testing of the catalytic activity of the complexes are presented in Table 4. The reactions were complete in 3-30 minutes with the formation of 4′-methoxy[1,1′-biphenyl]-3-carboxylic acid (190), the target product of the cross-coupling, with yields of 96-100%. In each case, the formation of palladium black did not occur until the end of the reaction. Analysis of the reaction mixtures by TLC at the time of separation of the Scheme 72 Synthesis of N-aryl(isothiazol-3-yl)methyleneimines (aromatic azomethines) and amines

Review Syn thesis
palladium black consistently showed the absence of aryl halide. The solution itself remained almost colorless, which indirectly indicates a low content of colloidal (nanoscale) palladium in the reaction mixture and products.
According to the obtained data, the palladium complexes with one ligand (LPdCl 2 ) were significantly more active than those with two ligands (L 2 PdCl 2 ). The complex with the isothiazole derivative 200 was the most active among all the complexes tested, and its activity was especially noticeable at 20-35 °C. It should also be noted that the formation of a small amount of the arylboronic acid homocoupling product, 4,4′-dimethoxy-1,1′-biphenyl (with yields of 1-3%), was observed in the reactions in all cases. Since the reactions were carried out in the absence of an inert atmosphere, it is possible that the by-product was formed because of oxidation of the starting arylboronic acid by aerial oxygen during the catalysis with palladium, but the contribution of this process is considered negligible. Complex 200 was used for the preparation of a heterogeneous siliconoxide-supported catalyst, and its catalytic properties were almost as good as the complex itself and it was able to withstand at least 10 catalytic cycles. 154 The observed temperature dependence of the catalytic activity of the described isothiazole complexes can be used to control the selectivity of the cross-coupling reactions in molecules with several reaction centers. Isothiazole palladium complexes are suitable for chemical and chemical-pharmaceutical processes in cases where the synthesis of the target substances is carried out using the Suzuki reaction and high purity requirements are imposed on the final product.
We are confident that the data on isothiazole-metal complexes summarized above, as well as the information on the catalytic and biological activity of their representatives, can stimulate further research in this very promising area. At the same time, we believe that while the synthesis of new metal complexes of the isothiazole series and the study of their properties definitely deserves the attention of modern researchers, so also does the study of the practical utilization of the isothiazole complexes that were previously described in the literature.
The above information on isothiazole complexes, as far as we know, is comprehensive. In an earlier review on the coordination chemistry of thiadiazoles, thiazoles and isothiazoles, isothiazole-metal complexes were given little more than one page, with only five papers on this topic being considered. 155

Conclusion
The presented and summarized data, published mainly over the past 18 years, demonstrates the intensive development of isothiazole chemistry and highlights the rich potential of isothiazole derivatives both for organic synthesis and practical use.
New data on the design of isothiazole heterocycles and the synthesis of isothiazole derivatives has been considered from the standpoint of retrosynthetic analysis, which allows four rational approaches for the formation of the isothiazole rings to be distinguished: intramolecular cyclization, (4+1)-heterocyclization, (3+2)-heterocyclization and synthesis based on other heterocyclic compounds. Such classification enables a consistent and logical understanding of the available approaches to obtaining substituted isothiazoles, and in some cases, to predict the most rational synthetic methods thereof.
The largest part of the published information is covered in the section dedicated to the target functionalization of substituted isothiazoles. This data demonstrates the rich possibilities of the developed strategies for successive transformations of isothiazole derivatives. Chlorinated isothiazoles seem particularly promising as starting compounds in this regard.
The logical continuation of such functionalizations is a separate section devoted to biologically active isothiazoles. In recent years, a large number of molecules containing the isothiazole fragment have been proposed as bioactive substances capable of selectively conjugating with key enzyme sites. There are various strategies for the formation of such molecules, which have been illustrated in detail. The most common strategy is sequential multistep synthesis based on isothiazole cores with reactive substituents. This method is used for the synthesis of a number of isothiazoles possessing significant antimitogenic activity. Sufficiently high interest is represented by published data on isothiazoles that exhibit synergistic effects in compositions with known anticancer drugs and pesticides. It is hoped that the research in this field will continue to develop rapidly and will unite the efforts of both chemists and specialists in the fields of biochemistry and medicine.
A separate section is devoted to isothiazoles in the synthesis of transition-metal complexes and in metal-complex catalysis. There is a great future for research in this field of isothiazole chemistry, especially in the development of metal-complex catalysts for cross-coupling reactions. The data on the metal complexes of the isothiazole series was previously sparse and fragmentary, and information on their possible practical use had not been summarized. Much remains to be done in this area in terms of improving metal-complex catalysts for effective use in aqueous media ('green chemistry') and in finding appropriate methods for A. V. Kletskov et al.

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determining their structures. The biological activity of metal complexes of isothiazoles remains an almost untouched field of research.
We hope that the data presented and analyzed herein will serve as a stimulus for further studies in the field of isothiazole chemistry, and that it will be useful not only to those who work in the field of heterocyclic chemistry and medicinal chemistry, but also to all specialists in modern organic synthesis as an inspiration and a source of ideas for further research.

Funding Information
The publication has been prepared with the support of the "RUDN University Program 5-100". ( ) A. V. Kletskov et al.