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

SYNTHESIS0039-78811437-210X Georg Thieme Verlag Stuttgart · New York 2020, 52, 159–188 review 159 en

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Alexey V. Kletskov*a 0000-0002-6979-545X Nikolay A. Bumaginb Fedor I. Zubkova 0000-0002-0289-0831 Dmitry G. Grudinina Vladimir I. Potkinc a Organic Chemistry Department, Faculty of Science, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation [email protected] b M.V. Lomonosov Moscow State University, Leninskii Gory, 1/3, Moscow 119991, Russian Federation [email protected] c Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Surganova Str., 13, 220072, Minsk, Belarus [email protected]

Received: 21.07.2019 1 Introduction Accepted after revision: 09.09.2019 Published online: 17.10.2019 DOI: 10.1055/s-0039-1690688; Art ID: ss-2019-z0406-r The search for new chemical compounds with useful License terms: properties and the development of rational ways to synthe- © 2020. The Author(s). This is an open access article published by Thieme under the size them are priority tasks in chemical science, with the terms of the Creative Commons Attribution License, permitting unrestricted use, dis- synthesis of biologically active chemical compounds for tribution and reproduction, so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) medicine and agriculture being of particular importance. In this respect, isothiazole derivatives, which have demon- Abstract The chemistry of isothiazoles is being intensively developed, strated high potential in the design and synthesis of a wide which is evidenced by the wide range of selective transformations in- range of biologically active substances, are of great interest. volving the isothiazole heterocycle and the high biological activity of its Among natural bioregulators, isothiazole-containing com- derivatives that can be used as effective new drugs and plant protection chemicals. Some representatives of isothiazoles have proven to be syn- pounds are present in only a few examples: the phytoalex- ergists of bioactive substances, which opens the way to lower the doses ins (brassilexin1 and sinalexin),2 a prostaglandin release in- of drugs used and is especially important in cancer chemotherapy. In hibitor (pronkodin A),3 and a cytotoxin (aulosirazol).4 How- the framework of the present review, the accomplishments in the ever, this does not impede the use of the isothiazole nucleus chemistry of isothiazoles over the past 18 years are examined, whilst current strategies for the synthesis of isothiazole-containing molecules in the creation of a wide variety of bioactive substances; for and key directions of studies in this field of heterocyclic chemistry are example, compounds exhibiting anti-poliovirus activity discussed. Considerable attention is paid to chlorinated isothiazoles and have been synthesized.5 Promising compounds for the strategies for their use in the synthesis of biologically active substances. treatment of Parkinson’s disease have also been identified,6 In addition, a comprehensive review of existing literature in the field of and recently, derivatives suitable for cancer7–12 and diabe- metal complexes of isothiazoles is given, including the results and pros- 13–15 pects for the practical use of isothiazole–metal complexes as catalysts tes therapy have been obtained, as well as microbi- 16,17 for cross-coupling reactions in aqueous and aqueous–alcoholic media cides. The isothiazole heterocycle in microbicides can (‘green chemistry’). protect the molecule from the action of enzymes,18,19 there- 1 Introduction by extending the time of the molecule’s action, which in 2 Synthesis by Ring-Forming Reactions turn makes it possible to administer additional doses of the 2.1 Intramolecular Cyclization 2.2 (4+1)-Heterocyclization drug less frequently. A promising class of isothiazole-con- 2.3 (3+2)-Heterocyclization taining inhibitors of the nuclear bile acid receptor FXR has 2.4 Syntheses by Ring Transformations been found, representatives of which can be used in the 3 Isothiazoles by Ring Functionalization Reactions: Nucleophilic treatment of liver diseases.20 Some isothiazoles can be suc- Substitution, Cross-Coupling and Side-Chain Functionalization cessfully used to create competitive antagonists of insect 4 Selected Syntheses of Biologically Active Isothiazole Derivatives 21 5 Isothiazoles in the Synthesis of Transition-Metal Complexes and GABA receptors, and among the isothiazoles, effective in Metal-Complex Catalysis plant growth regulators22 and fungicides23,24 have been 6 Conclusion found.

Key words heterocycles, isothiazoles, bioactive heterocycles, catalysis, cross-coupling, palladium, transition metals, complexes

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Biographical Sketches

Alexey Viktorovich Kletskov Academy of Sciences of Belarus. heterocyclic chemistry, the obtained his Master’s degree He is currently a postdoctoral synthesis and study of metal from the Graduate School of the researcher at the Department complexes with substituted iso- National Academy of Sciences of Organic Chemistry at RUDN thiazoles and isoxazoles, and the of Belarus in 2013, and subse- University (Russia). His current synthesis of novel heterocyclic quently received his Ph.D. in scientific interests include the substances with high potential 2017 from the Institute of Phys- development of novel synthetic for practical applications. ical Organic Chemistry, National methodologies in the field of

Nikolay Alexandrovich Prize in 1991 and earned the ti- current scientific interests are Bumagin received his Ph.D. in tle of Professor in 1992. He is focused on homo- and hetero- 1979 and his D.Sc. degree in currently Head of the Transition geneous catalysis in organic 1986 from M.V. Lomonosov Metal Catalysis Group at the De- synthesis, the chemistry of het- Moscow State University. He partment of Chemistry of Mos- erocyclic compounds, and was awarded the Nesmeyanov cow State University. His green chemistry.

Fedor Ivanovich Zubkov chemistry in 2000. From 2001 His scientific interests include earned his Master’s degree in until present, he has worked as cycloaddition reactions, trans- chemistry at the Peoples’ a docent at the Organic Chemis- formations of oxygen- and ni- Friendship University of Russia try Department of the Peoples’ trogen-containing heterocycles, in 1997, followed by his Ph.D. in Friendship University of Russia. and total synthesis.

Dmitry Guennadievich Gru- chemical and pharmaceutical new organic materials for elec- dinin earned his Ph.D. in chem- companies in Russia, South Ko- tronics, as well as pharmaceuti- istry at the Peoples’ Friendship rea, and Canada. His scientific cal analysis. University of Russia in 2000. interests include the synthesis Since 2001 he has worked for of heterocyclic compounds and

Vladimir Ivanovich Potkin State University. In 2000 he was Chemistry, National Academy of graduated from Gorky State elected as a Corresponding Sciences of Belarus. His scientif- University (now Nizhny Member of the National Acade- ic interests include heterocyclic Novgorod, Russia) in 1975. He my of Sciences of Belarus, and in chemistry, the synthesis and received his Ph.D. in 1982 from 2009 he earned the title of Pro- study of biologically active com- the Institute of Physical Organic fessor of Chemistry. Currently, pounds, and metal complexes Chemistry of the Belorussian he is the Head of the Organic of isothiazoles and isoxazoles Academy of Sciences, and his Chemistry Department at the and their properties. D.Sc. in 1996 from Belarusian Institute of Physical Organic

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In a few reports, isothiazoles have been studied for pos- information on metal complexes with isothiazole ligands is sible use as ligands for metal complexes. At the same time, considered in the final part of the literature review, and despite the fact that metal complexes in general have prov- will, in our opinion, provide a comprehensive picture of de- en themselves useful in creating a wide range of new tech- velopments in the field of isothiazole metal complexes, in- nologies and biologically active substances, ways to apply cluding information that has escaped the attention of other isothiazole complexes in practice have rarely been investi- authors for one reason or another. gated. 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 2 Synthesis by Ring-Forming Reactions shown,25–27 are the exception. The above facts demonstrate the high potential of using Different approaches can be used to classify the meth- isothiazole heterocycles in the design and synthesis of com- ods for producing isothiazoles, and the classification pro- pounds for different purposes and indicate broad prospects posed herein by us is based on retrosynthetic analysis. This for the further development of isothiazole chemistry, espe- allows us to build a consistent and logical understanding of cially coordination chemistry. Within the framework of the the approaches to the production of substituted isothi- present review, achievements in isothiazole chemistry over azoles, and in some cases, to provide the most rational the past 18 years will be covered, and references from pre- methods for their synthesis. However, the predictive effi- vious years will be mentioned only to create a holistic pic- ciency of this retrosynthetic classification is low in the case ture of the recent research progress in this field. of complex reactions with an unobvious mechanism, as the This review deliberately does not include data on isothi- proposed classification does not always reflect the true azolinones, 1,1-isothiazoledioxides, and dihydroisothi- mechanism of the reaction. Yet, it does allow us to visualize azoles, and only some examples related to condensed iso- the possible conditions for the preparation of isothiazoles, thiazole-containing systems are considered. This is due to representing the formation of an isothiazole ring from frag- the fact that, in our opinion, such compounds, although be- ments containing a certain number of atoms. It certainly ing related, differ significantly in their chemical properties does not cover all possible methods for the preparation of from 1,2-thiazole, and a consideration of their chemical substituted isothiazoles, but it reflects the key stages of transformations as well as their practical use would lead to most approaches to their synthesis. Overall, retrosynthetic a significant increase in the volume of this paper and dis- analysis allows us to distinguish four rational approaches tract from the subject being reviewed. However, special at- for the formation of the isothiazole ring. tention is paid to halogen-containing isothiazoles, and in particular, chlorinated isothiazoles, which are convenient 2.1 Intramolecular Cyclization synthetic building blocks that allow the ability to obtain a wide variety of substituted isothiazoles capable of acting An example of such an approach is the synthesis of sub- both as biologically active substances and as ligands for stituted isothiazoles 1 by forming an S–N bond in an S–C– metal complexes. C–C–N fragment via oxidative cyclization of substituted 3- In the general context of the chemistry of heterocyclic aminopropenethiones 2 under the action of various re- compounds, data on the chemical properties of isothiazoles agents. The classic version of this approach uses iodine;39 are presented in review articles,28–30 whilst isothiazoles however, methods using other oxidizing agents, such as hy- have been directly reviewed,31–34 and covered in a mono- drogen peroxide, have recently become very popular graph35 devoted to biologically active isothiazoles. There (Scheme 1).40,41 Hydrogen peroxide, in particular, was used are also reports summarizing data on isothiazole-ring-con- in the formation of the isothiazole nucleus at the penulti- taining compounds in crop protection,36 the involvement of mate stage in the synthesis of a series of allosteric antago- the isothiazole core in cross-coupling reactions,37 and [4+2] nists of the mGluR1 receptor, and which are promising cycloadditions of isothiazole derivatives.38 compounds for the treatment of various pain syndromes.40 There are a significant number of methods for isothi- 1 oxidant R R1 R2 azole synthesis, and so in order to present the material con- reflux or r.t, 2–8 h R R2 sistently as well as to form a holistic view of isothiazole 35 N Et2O (I2 + K2CO3) R S NH2 39 S chemistry, it would be rational to first consider the ap- MeOH (30% H2O2) 2 40 1 (30–93%) proaches to isothiazole cycle design, highlighting the main Et2O (30% H2O2) 35,39 40 synthetic strategies. Next, some methods for the function- R = NH2 , alkyl, aryl, hetaryl R1 = H 35, Me 39, CN 40 alization of isothiazoles will be reviewed, and after that, R2 = alkyl 35, aryl 39, Me, aryl 40 targeted syntheses of biologically active agents that are Scheme 1 Synthesis of isothiazoles through oxidative cyclization of promising for practical use will be considered. The available substituted 3-aminopropenethiones

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Along with iodine, bromine can be used for effective ox- Ar Ar HN HN idative cyclization. Thus, the isothiazoles 4, which are in- N H N Et3N, 25 °C 2 O hibitors of hepatitis C polymerase NS5B as well as precur- O O N O N sors of the inhibitors of the important cancer therapy ki- S S nases Chk2 and MEK1, have been synthesized by oxidizing OEt OEt 7 8 N-substituted propanethioamides with molecular bromine in ethyl acetate (Scheme 2).42–44 Scheme 4 Formation of isothiazole core through nucleophilic cyclization in the 4-aminoisothiazole synthesis

1 CN 1 R H R NC OH N NH2 Br2 As an important example of the formation of the isothi- N S O EtOAc N 2 S azole nucleus by the closure of a five-membered fragment, R2 R H 3 4 (70–90%) a recently proposed method for the synthesis of reactive 3- chloroisothiazole (9) should be mentioned. The 3,3′-disul- Scheme 2 Bromine as the efficient reagent for cyclization of 3-aminopropenethiones fanyldipropanoic acid diamide 10 can be cyclized to give 3- chloroisothiazole (9) by the action of phosphorus oxychlo- ride in toluene (Scheme 5).47 From a preparative point of view, a promising variation of this approach is the oxidation of isothiazole precursors O POCl3, 10 °C,12 h Cl S NH then 4 h, 100 °C H N S 2 without the use of a solvent. Thus, it has been shown that 2 PhMe N O S 10 the solvent-free oxidative cyclization of 3-aminopropene- 9 (83%) thiones 5 can be carried out by using chromium trioxide 45 Scheme 5 Preparation of 3-chloroisothiazole from the 3,3′-disulfa- supported on silica gel (Scheme 3). It should be noted that nyldipropanoic acid diamide 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 2.2 (4+1)-Heterocyclization microwave irradiation. In the framework for this approach, we can consider the NH2 S NC R1 CrO3–SiO2 heterocyclization of synthetic equivalents of synthons, R1 R2 which are formed when one atom is removed from the iso- 2–3 h, 20 °C R2 N CN or S thiazole ring, with the synthetic equivalents of the corre- 56MW, 1–2 min (64–90%) sponding atom. The most relevant examples of the hetero- 1 R = Me, Ph, 4-MeC6H4 2 cyclization of compounds corresponding to synthons with R = alkyl, -CH2OPh, -CH2-(2,4-Cl2C6H3) 2-thienyl, 2-furyl one heteroatom removed from a 1,2-thiazole ring are given Scheme 3 Oxidative ring closure of 3-aminopropenethiones under below.

CrO3/SiO2 system action Recently, an original method for producing substituted furo[2,3-c]isothiazoles 11 from 2-[amino(3-aryl-2-cyano- oxiran-2-yl)methylene]malononitriles 12 in an aqueous di- The closure of the C–N–S–C–C fragment with the forma- oxane medium with sodium thiocyanate as a sulfur donor tion of a C–C bond can serve as another interesting example was described (Scheme 6).48 It is noteworthy that in previ- of intramolecular cyclization. Using this approach, the for- ous studies the only proposed method for the synthesis of mation of an isothiazole ring in the synthesis of the VEGFR1 furo[2,3-c]isothiazoles was via intramolecular nucleophilic and VEGFR2 inhibitors was carried out.46 The intramolecu- substitution with the participation of azide and thione frag- lar condensation of an activated methylene fragment with a ments.49,50 cyano group in compounds 7 led to isothiazoles 8, of which It was found that an S2Cl2 molecule can act as a sulfur further directed modification allowed the target com- donor in the synthesis of isothiazoles, as was shown when pounds to be obtained (Scheme 4). preparing dinitrobenzo[c]isothiazole 13 from 2-amino-4,6- dinitrotoluene (14) (Scheme 7).51 The key value of the

CN CN NH2 NaSCN O Ar = Ph 82% NH2 70 °C, 1 h NC CN Ar = 4-FC6H4 76% NC CN O Ar = 4-MeC6H4 83% CN aqueous O H2N H Ar Ar = 2-ClC6H4 86% dioxane – CN N Ar = 3-ClC H 89% H Ar SCN Ar S 6 4 12 11 Scheme 6 Formation of furo[2,3-c]isothiazoles through rearrangement of substituted cyanooxirans

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NO2 1. S2Cl2, DABCO, 20 °C, 72 h NO2 S 2 O S NH4OAc, 100 °C, 3–8 h, air N R Me 2. Et3N R1 R2 AcOH S R1 O N NH N 2 2 O2N 20 19 (70–85%) 14 13 (90%) Scheme 10 Use of -keto thioesters for 3,5-disubstituted isothiazole Scheme 7 Sulfur dichloride as the reagent for construction of ben- synthesis zo[c]isothiazole

Substituted isothiazoles 21 were able to be isolated as nature of the base used in the first stage of the reaction was minor products when -keto dithioesters 22 were reacted revealed: when N-ethyldiisopropylamine or triethylamine with ammonia, which also acts as a donor of the nitrogen were used individually, the yield of the desired isothiazole atom to construct a 1,2-thiazole heterocycle. Additionally, it 13 did not exceed 18%. However, with the sequential intro- was found that copper acetate promotes formation of the duction of 1,4-diazabicyclo[2.2.2]octane (DABCO), and then isothiazole heterocycle (Scheme 11).55 triethylamine, a 90% yield of isothiazole 13 was achieved. O S S A recently proposed method for the synthesis of 3,4-di- O S aq NH4OH N + R2 1 chloroisothiazole-5-carbonitrile (15) from succinonitrile R1 SR2 100 °C R NH2 R1 (16), sulfur, and chlorine gas is of considerable industrial in- 22 75–85% 21 (5–15%) terest (Scheme 8).52 The method avoids the use of aprotic R1 = Ar; R2 = Me, Et polar solvents such as DMF, which increase the cost of pro- Scheme 11 Short pathway to 5-thioisothiazoles duction and at the same time increase the environmental hazards. Nitrile 15 is not only a representative of a reactive 2.3 (3+2)-Heterocyclization class of chlorinated isothiazoles but is also a precursor of 3,4-dichloroisothiazole-5-carboxylic acid 2-cyanoanilide, This approach involves the interaction of two chemical also known as isotianil, a commercial fungicide. compounds that act as suppliers of diatomic and triatomic fragments to form an isothiazole ring.

Cl Cl S, Cl2, 120–125 °C, 22 h Recently, a series of 4-arylisothiazoles 24, as inhibitors NC CN N of the detoxification of the isothiazole-containing brassilex- NC S 16 15 (76%) in fungicide in L. maculans fungus, was synthesized using this approach. Thus, the corresponding ,-unsaturated al- Scheme 8 Synthesis of the isotianil precursor dehydes 23 were introduced into the reaction with ammonium thiocyanate in dimethylformamide to give the 4- Recently, 3,5-aryl-substituted isothiazoles 17 have been arylisothiazoles 24 (Scheme 12).56 The ammonium thiocya- synthesized based on unsaturated N-sulfonyl ketimines 18, nate in the reaction acts as a donor of the N–S fragment. •– via the cascade addition of an S3 radical anion and subse- 53 Ar Ar quent reductive detosylation (Scheme 9). The lowest yield NH4SCN, 16 h 1 (14%) was observed for the thienyl derivative (R = 2-thie- DMF, 70 °C N OHC Cl S 2 nyl, R = 4-MeС6H4). 23 24

Ar = Ph (54%), 2-ClC6H4 (30%), 2-MeC6H4 (25%) K S (2 equiv) 2 Ts 2 R N K CO (0.5 equiv), 0.5 h N 2 3 S Scheme 12 Heterocyclization of 3-chloroacroleins under NH4SCN action R1 R2 DMF, 130 °C, air R1 = Ar, 2-thienyl; R2 = Ar R1 18 17 (14–51%) Scheme 9 A route to 3,5-diarylisothiazoles via the cyclization of ket- According to a similar scheme, isothiazoles 25 were ob- imines tained from (Z)-3,4-diaryl-3-chloroacrylaldehydes 26. Com- pounds 25 demonstrate inhibitory activity against COX-1 A new protocol for the synthesis of 3,5-disubstitut- and COX-2 cyclooxygenases, 5-LOX lipoxygenase,57 and po- ed/annulated isothiazoles 19 utilizing -keto dithio- tentially against mitogen-activated p38 protein kinase. esters/-keto thioamides 20 and NH4OAc under metal-free They are also considered as promising candidates for in vi- conditions was reported in 2016 (Scheme 10).54 The strate- tro and in vivo testing for anti-neuroinflammatory activity 58 gic (4+1) annulation initiated by NH4OAc is carbon- and neuroprotective properties (Scheme 13). economic and relies on a sequential imine formation/ cyclization/aerial oxidation cascade forming consecutive C–N and S–N bonds in one pot.

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1 2 MW (200 W) R R R1 R2 Ph MeO2C Ph O 10 min, 160 °C DMAD Ph CNS NH SCN N 4 N O – CO2 S MeO2C S EP acetone, reflux, 4 h 29 30 (56%) – HCN Cl S Ph Ph N MeO2C O 31a+ 31b N 26 1 25 (40–70%) N R = OCH3, CH3, Cl, F MeO2C S S 2 48% R = OCH3, CH3, Cl, SO2CH3 Scheme 13 3-Chloroacrylaldehydes in the synthesis of arylisothiazoles Scheme 15 Phenyloxothiazolone reaction with ethyl propiolate and DMAD under microwave irradiation

The 1,3-dipolar cycloaddition reaction, also known as copper-catalyzed direct asymmetric conjugate addition of the Huisgen cycloaddition, represents another method that allyl cyanide (33) to ,-unsaturated thioamides 34 can be used for isothiazole cycle formation and should be (Scheme 16).61 mentioned within the framework of the regarded approach. S The reaction of functionalized acetylenes with nitrile sul- [Cu(MeCN)4]PF6 phosphine ligand Bn2N R fides—reactive dipoles generated from 2-oxo-1,3,4-oxathi- Li(4-MeOC6H4O) S R 34 Ph P=O (10 mol%) azoles in aprotic polar solvents such as chlorobenzene and + 3 H Bn2N toluene—can serve as an example. In particular, 3-phenyli- 35 CN sothiazol-5-carboxylic acid 27a and 3-phenylisothiazole-4- CN 33 Li(4-MeOC6H4O) carboxylic acid 27b were obtained from phenyloxathi- S N (1.0 equiv), TEMPO (0.3 equiv) azolone 28 by this method (Scheme 14), and the synthe- Bn2N if R = Ph, yield = 34% sized products showed low in vitro cytotoxicity along with R 97% ee (one pot) the ability to protect cells from being infected with HIV-1.59 32 Scheme 16 An example of an asymmetric cyclocondensation resulting N S OH in isothiazoles

S O O N 27a It is important to note that the yield of the target isothi- O 1. HC C CO2Me BnO xylene, reflux, 26 h azoles 32a–d increased with the introduction of prelimi- N S 2. NaOH (1 M) nary isolated products of the allyl cyanides addition 35 to THF, r.t., 2 h ,-unsaturated thioamides into the reaction (Scheme 17). OBn 3. H+ O OH BnO 28 27b S R CuOTf (10 mol%) S N Li(4-MeOC6H4O) (1.1 equiv) Bn2N Bn N Scheme 14 The cycloaddition reaction between 2-oxo-1,3,4-oxathi- 2 TEMPO (0.1 equiv), PhMe/THF azole and methyl propiolate CN 20 °C, 24 h R 35 32a: R = Ph 69% 32a–d 32b: R = p-ClC6H4 73% The efficiency of using microwave irradiation in such re- 32c: R = Me 55% actions has been demonstrated. This method allows avoid- 32d: R = i-Pr 82% ing long reaction times and, in some cases, reduces the Scheme 17 Optimal conditions for the asymmetric synthesis of isothi- amount of by-products and increases the yields of the tar- azoles get compounds.60 Thus, phenyloxothiazolone 29 was reacted with dimethyl acetylenedicarboxylate (DMAD) in chlo- 2.4 Syntheses by Ring Transformations roform under microwave irradiation to form adduct 30 in a yield of 56%, while the reaction with propiolic acid ethyl es- Formally, reactions for the synthesis of substituted iso- ter (EP) for 10 minutes resulted in a mixture of regioiso- thiazoles on the basis of other heterocycles can be consid- meric isothiazoles 31a and 31b with a total yield of 48% ered within the framework of the three previous approach- (Scheme 15). The authors noted that a low level of regiose- es, since they usually proceed through the stage of breaking lectivity was a common factor for reactions of nitrile sul- the bonds in the initial cyclic molecule and subsequent het- fides, in contrast to reactions of nitrile oxides, which led to erocyclization of the resulting intermediate. However, in isoxazole-5-carboxylates as the main products. This effect our opinion, it is advisable to single out the reactions that is usually attributed to a higher degree of HOMO-dipole result in the transformation of other heterocycles into iso- control for nitrile sulfide reactions. thiazoles as a separate approach. This is due, first of all, to Finally, a very interesting and original example of (3+2)- the rather complicated mechanism of such reactions, and to heterocyclization is the recently proposed method of asym- a certain non-obviousness in choosing possible synthetic metric synthesis of condensed isothiazoles 32 through a equivalents when analyzing the structures of the desired isothiazoles.

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1. POCl Recently, an original method for the synthesis of 3,4,5- O R2 3 R NH R2 2. NH3, CH3CN functionalized isothiazoles 40 was developed through rho- N R1 N R1 64 R S S dium-catalyzed transannulation of 1,2,3-thiadiazoles 41 36a–i 37a–i with alkyl, aryl, and hetaryl nitriles 42 through the forma- 1 2 37a: R = 4-Me-C6H4-CH2-; R = H; R = H 13% 1 2 tion of a rhodium -thiavinyl carbenoid. The authors sug- 37b: R = 4-Cl-C6H4-CH2-; R = H; R = H 33% 1 2 37c: R = -CH2CO2Et; R = H; R = H 59% gest that in the reaction with nitriles, the -thiavinyl car- 37d: R = Me; R1 = Cl; R2 = H 61% benoid acts as an equivalent of a 1,3-dipole with reversed 1 2 37e: R = Et; R = Cl; R = H 55% polarity (Scheme 20). 37f: R = Bn; R1 = Cl; R2 = H 50% 37g: R = Me; R1 = Cl; R2 = Cl 43% Later, this method was successfully used by the same 37h: R = Et; R1 = Cl; R2 = Cl 40% authors to synthesize a series of bi-, tri-, and tetracyclic iso- 1 2 37i: R = Bn; R = Cl; R = Cl 55% thiazoles 43 with good to excellent yields through the intra- Scheme 18 Preparation of 3-aminoisothiazoles on the base of 3-isothi- molecular transannulation of cyanothiadiazoles 44 azolones (Scheme 21).65 Isothiazoles can be obtained on the basis of 1,2,3-dithi- R azoles. Recently, improved conditions for the ring transfor- R N X EtO2C X mation of 1,2,3-dithiazoles 45 into isothiazole-5-carboni- EtO C 2 S I CH CN, hv 66 3 N triles 46 were reported (Scheme 22). Shorter reaction S 39 38a–d times correlated with higher isothiazole yields and the use 38a: X = S, R = H (96%, 10:1 isomers of 2- and 3-subsituted thiophene) of THF as solvent in almost all cases. 38b: X = S, R = Br (36%); 38c: X = -CH=CH-, R = H (90%); 38d: X = O, R = H (89 %) R Scheme 19 The tandem photoarylation/photoisomerization of 2-iodo- HHal (gas) or R Hal NC Cl BnEt NCl (cat.) thiazole-5-carboxylic ethyl ester 3 THF or Et2O N S N NC S S Hal = Cl, Br An important example of this approach is the synthesis 45 46 (64–100%) of isothiazoles based on N-substituted 3-isothiazolones. 3- R = H, Cl, Br, CO2Me, CO2Et, CN

Isothiazolones 36a–i can be transformed into functional- Scheme 22 Preparation of 5-cyanoisothiazoles through the acid- ized 3-aminoisothiazoles 37a–i by sequential treatment catalyzed RORC reaction with phosphoryl chloride and ammonia (Scheme 18).62 Among the methods for the synthesis of isothiazoles based on other heterocycles, the recently proposed method 3 Isothiazoles by Ring Functionalization for the synthesis of 3-phenyl(heteroaryl)isothiazole-3-car- Reactions: Nucleophilic Substitution, Cross- boxylic acid ethyl esters 38a–d via the tandem photoaryla- Coupling and Side-Chain Functionalization tion and photoisomerization of 2-iodothiazole-5-carboxylic acid ethyl ester 39 is of considerable interest (Scheme 19).63 Next, we will consider some methods for the synthesis It should be noted that no rearrangement occurred in the of isothiazoles in which reagents containing the formed iso- case of a similar 2-chloro-substituted thiazole. thiazole ring are involved. The chemical properties of isothiazoles are largely defined by the presence of the delocal- ized -orbitals system. Isothiazoles have a high degree of cat. [Rh(COD)Cl] R1 2 R1 R3 DPPF aromaticity in accordance with the HOMA (harmonic oscil- N 3 + R N lator model of aromaticity) criterion. In this respect, among R2 N PhCl, 130 °C, – N2 R2 N S S the 1,2-azoles, isothiazoles occupy an intermediate position 41 42 40 (up to 99%) R1 R1 between isoxazole and pyrazole, being much more aromatic than isoxazoles, but less so than pyrazoles. Isothiazole 2 2 R S R S derivatives are also more aromatic than thiazole deriva- 1 2 3 R = CO2Et, Ph; R = CO2Et, Ar; R = alkyl, aryl, hetaryl tives. Positions 3 and 5 of the isothiazole ring are favorable Scheme 20 Rhodium-catalyzed transannulation of 1,2,3-thiadiazoles for the attack of nucleophilic reagents, while position 4 is

R2 R3 2 3 R4 R R R4 X = NH, NMe, O; Y = O, H X m cat. [Rh(COD)Cl]2 X 2 DPPF m m = 0, 1; n = 0, 1, 2 n C N Y Y n R 1= aryl, alkyl, 2-furyl, 2(3)-thienyl N PhCl, 130 °C, – N 2 R2, R3, R4 = H, alkyl, aryl 1 N 1 N R S R S 44 43 (up to 99%)

Scheme 21 Intramolecular cyclization of cyanothiadiazoles in the synthesis of annulated isothiazoles

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Syn thesis A. V. Kletskov et al. Review preferential for the attack of electrophilic agents. It should O O R1 1 1 be noted that position 5 of the isothiazole ring is more ac- S O R S R S O N + N N + N (minor) tive in nucleophilic substitution reactions than position 3. PhSO2 Ar CH2Cl2 In some cases, interactions with nucleophilic and electro- NHR r.t., 2–6 h NHR NHR philic reagents may lead to the ring-opening of the isothi- 51 52 50 53 azole.33 R1 = H, Cl; R = Me, Bn, Ph (55–76%) (10–15%) The achievements in the development of methods for Scheme 24 Oxidation of the sulfur atom in 3-aminoisothiazoles with the functionalization of the isothiazole nucleus and advanc- arylsulfonyloxaziridines es in the transformation of the side chains of the heterocycle, without involving the heterocycle itself in the reaction, In 2019, the same group developed an advanced ap- will be considered separately. Significant attention will be proach for the synthesis of chiral 3-amino-substituted iso- paid to the development of the chemistry of halogen-sub- thiazole sulfoxides by utilizing (+)- and (–)-[(8,8-dichloro- stituted isothiazoles, which are highly reactive synthetic camphoryl)sulfonyl]oxaziridine under microwave irradia- blocks, allowing the ability to obtain polyfunctional isothi- tion.71 azoles with a wide variety of substituents. Relatively little work in the literature is devoted to the Fairly recently, the possibility of direct oxidative alke- transformations of chlorine-substituted isothiazoles; how- nylation of the isothiazole heterocycle at the unsubstituted ever, these compounds enter into similar reactions to their position 4 was investigated, and it was found that the reac- bromine and iodine analogues, but often under more severe tions proceeded with low yields. This was demonstrated by conditions and react at slower rates. the example of the reaction of 3-methyl-5-phenylisothi- Thus, 3,5-dichloro-4-cyanoisothiazole (54) reacts regio- azole (47) with n-butyl acrylate (48).67 In addition, along specifically with phenylboronic acid by substitution of the with product 49, 52% of the initial isothiazole 47 was recov- chlorine at position 5 and gives 5-phenyl-3-chloro-4-cy- ered from the reaction mixture (Scheme 23). anoisothiazole (55) in a high yield. In the same way, substitution of the chlorine at position 5 proceeds with the use of O Me 10% Pd(OAc)2 potassium phenyltrifluoroborate (Scheme 25). 3,5-Dibro-

O BuO Cu(OAc)2 (2 equiv) + Me mo-4-cyanoisothiazole reacts similarly, but the reaction N Ph OBu DMA, 120 °C 72 S N proceeds at a faster rate. Ph S 47 48 49 (15%) A. PhB(OH)2, KF, 18-crown-6, reflux

Scheme 23 Oxidative alkenylation of the isothiazole ring NC Cl Pb(OAc)2, PhMe NC Cl

N N Cl S B. PhBF3K, K2CO3, 18-crown-6, reflux Ph S It should be noted that the introduction of isoxazole, an 54Pb(OAc)2, PhMe 55 (A: 99%, B: 97%) isothiazole heteroanalogue, to the reaction under the same conditions led to the formation of the target alkenyl isoxaz- Scheme 25 Selective arylation of 3,5-dichloro-4-cyanoisothiazole oles, with yields of 50–68%. Because of this, the Heck reaction using haloisothiazoles In some cases when using chlorine derivatives of isothi- remains the preferred method of alkenylation of the isothiazoles, it is possible to synthesize the target compounds azole heterocycle, despite the moderate yields of the corre- with yields greater than those obtained when using bromo sponding alkenyl isothiazoles and the formation of a notice- derivatives. able amount of by-product.68 In recent years, considerable Thus, it was found that 3-bromo(chloro)isothiazole-4- attention has been paid to metalation reactions of the iso- carbonitriles 56a and 56b allow direct arylation at position thiazole core for the subsequent preparation of reactive iso- 5 of the heterocycle in the presence of silver fluoride to give thiazole blocks for cross-coupling reactions. Advances in the corresponding 5-phenylisothiazoles 57a and 57b this field of isothiazole chemistry have been discussed in (Scheme 26).73 Conditions for the preparative synthesis of detail by Nutaitis.69 diisothiazole derivatives 58a and 58b were also developed. A mild approach to synthesize 3-amino-substituted iso- Chlorine derivatives of isothiazole were formed in high thiazole sulfoxides 50 through oxidation of the correspond- yields, both in the case of arylation and in the synthesis of ing 3-aminoisothiazoles 51 with arylsulfonyloxaziridines diisothiazole derivatives. 52 has been reported (Scheme 24).70 Only minor amounts Recently it has been shown that with the introduction of dioxides 53 were formed under the described conditions. of pyrrolidine into the nucleophilic substitution reaction of The reactivity of the resulting isothiazole sulfoxides toward bromine in 3-bromo-4,5-dicyanoisothiazole (59), the main sulfur nucleophiles has been studied and resulted in the product was 2-[di(pyrrolidin-1-yl)methylene]malononitrile formation of 5-sulfanyl-substituted 4,5-dihydroisothi- (60), while the expected product, 4,5-dicyano-3-(pyrroli- azoles. din-1-yl)isothiazole (61), was either not formed at all or

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PhI (2 equiv), AgF (2 equiv) NC Hal din-1-yl)-3-chloroisothiazole (63) with an 80% yield Ph3P (10 mol%) (Scheme 28). Koutentis suggested that the most likely pre- N 57a,b [PdCl2(Ph3P)2] (5 mol%) S cursor of dinitrile 60 is 2-(pyrrolidin-1-yl)ethene-1,1,2-tri- NC Hal MeCN, reflux, 25 min carbonitrile (64), which was formed from the substituted N NC Hal isothiazoles 59 and 62 when interacting with pyrrolidine S [PdCl2(Ph3P)2] (20 mol%) AgF (2 equiv) S 56a,b N 58a,b via nucleophilic attack on the sulfur. The resulting 2-(pyrro- N S MeCN, reflux, 2 h lidin-1-ylthio)ethene-1,1,2-tricarbonitrile 65 then gives Hal = Cl: 57a (96%), 58a (69%) Hal CN trinitrile 64 on eliminating the sulfur atom. The subsequent Hal = Br: 57b (73%), 58b (67%) interaction of intermediate 64 with pyrrolidine leads to the Scheme 26 Aryl–aryl coupling of 3-halogen-substituted isothiazole-4- formation of dinitrile 60 (Scheme 29). carbonitriles

NC CN NC Hal NC CN R NH NC CN 74 2 was only formed in small amounts (Scheme 27). By vary- NC S – 1/8 S – HCN NC N – HHal 8 S NC NR2 R2N NR2 ing the temperature and duration of the reaction, the maxi- NR2 mum yield of isothiazole 61 reached 11%. 6564 60 R2NH R2NH = pyrrolidine Scheme 29 Elimination of the sulfur atom from 4,5-dicarbonitrile- NC CN NC Br N 3-halogeno isothiazoles under the action of secondary amines H NC N + N PhMe N N NC S NC N S The chemistry of chlorine-substituted isothiazoles was 5961 (0–11%) 60 (32–76%) developed in the Laboratory for Organoelement Com- Scheme 27 Nucleophilic substitution in 3-bromo-4,5-dicyanoisothi- pounds of the Institute of Physical Organic Chemistry at the azole National Academy of Sciences of Belarus. In the course of the research conducted at the laboratory, it was shown that At the same time, with the introduction of 4,5-dicarbo- isothiazoles containing chlorine atoms at positions 4 and 5 nitrile-3-chloroisothiazole (62) into a similar reaction, a of the heterocycle and an electron-withdrawing group at 37% yield of 4,5-dicarbonitrile-3-(pyrrolidin-1-yl)isothi- position 3, successfully enter into a nucleophilic substitu- azole (61) was achieved by varying the temperature and re- tion reaction. When this occurs, the chlorine atom at posi- action time (Scheme 28). tion 5 of the heterocycle is replaced, while position 4 remains unaffected. Research on the transformation path-

NC Cl NC CN ways of perchloroisothiazoles was initiated with 4,5- NC Cl N NC N H + + dichloro-3-trichloromethylisothiazole, on the basis of N PhMe N N N N NC S N S which many previously undescribed substituted 4- NC S chloroisothiazoles were synthesized. 62 61 (2–37%) 63 (24–80%) 60 (4–28%) Thus, the reactions of 4,5-dichloro-3-trichloromethyli- Scheme 28 Nucleophilic substitution in 3-chloro-4,5-dicyanoisothi- sothiazole (66) with N,S-nucleophiles were studied, and it azole was found that the interactions with heterocyclic amines in dimethylformamide resulted in 5-amino-substituted 3-tri- It is noteworthy that Kalogirou and Koutentis74 man- chloromethyl-4-chloroisothiazoles 67a–d,75 while reactions aged to find conditions under which the reaction of nitrile with alkyl(aryl)thiolates in ethyl alcohol led to the forma- 62 with pyrrolidine resulted in replacement of the nitrile tion of the corresponding 5-alkyl(aryl)sulfanyl-3-trichloro- function at position 5, forming 4-carbonitrile-5-(pyrroli- methyl-4-chloroisothiazoles 68a–c (Scheme 30).76

R1R2N = R1R2N = O 67a (96%) 67b (81%) Cl CCl3 R1R2NH, r.t., 8 h N N DMF 1 2 N H R R N S N Cl CCl3 67a–d 67c (96%) 67d (89%) N N Cl N S Cl CCl3 68a: R3 = n-Bu (54%) R3SNa, r.t., 1 h 66 68b: R3 = Bn (58%) EtOH 3 N 3 R S S 68c: R = Ph (61%) 68a–c Scheme 30 Nucleophilic substitution in 4,5-dichloro-3-trichloromethylisothiazole

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O Cl CCl3 Cl CO2H Cl CO2Me Cl CO H Cl CO2t-Bu H2SO4, 130–140 °C H2SO4 (cat.), reflux 2 SOCl2 Cl Cl t-BuOH, Py N air N MeOH N EtO S HO S HO S N CCl4 Et2O N Cl S N Cl S 69 71 (70%) 72 (92%) Cl S 74 77 (98%) 76 (95%) A: H /Pd (5 atm), MeOH, r.t., 6 h Cl CCl3 2 Cl CCl3 or R1R2NH (+ F–) A: 73 (90%) Cl CO2t-Bu B: 73 (95%) 25–80 °C BnO N HO N R2R1N = N , X N , S B: CF3CO2H, r.t., 6 h S ( )n 2 1 N DMF or DMSO or 70 R R N = S RHN-, RMeN-, R2N- NMP (R = alkyl; n = 1, 2; X = NH, O) 78 (15–95%) Scheme 31 A new synthetic approach toward 5-hydroxy-4-chloroisothiazoles Scheme 33 Nucleophilic substitution in tert-butyl ester of 4,5-dichloroisothiazole-3-carboxylic acid Starting from perchloroisothiazole 66, 5-ethoxy-4- chloro-3-trichloromethylisothiazole (69) and 5-benzyloxy- Other derivatives such as 4,5-dichloroisothiazole-3-car- 4-chloro-3-trichloromethylisothiazole (70) were synthe- boxylic acids 79,79 metallocenic80 and macrocyclic exam- sized by reactions with sodium ethylate and benzylate in ples,81 as well as various amides 80 were also obtained tetrahydrofuran, and were used in the development of new starting from acid chloride 77 (Scheme 34). synthetic methods toward 5-hydroxy-4-chloroisothiazoles 77 1 (Scheme 31). Thus, treatment of the 5-ethoxy derivative Cl CO2R R1OH, Py, r.t. 69 with hot sulfuric acid allowed 5-hydroxy-4-chloroiso- O Et2O N Cl S R1 = alkyl, aryl thiazolecarboxylic acid (71) to be obtained in a good yield, Cl Cl 79 (71–93%) R2 = H, alkyl, aryl, hetaryl which was then esterified under acidic conditions to form R3 = H, alkyl, aryl Cl N Cl CONR2R3 the methyl ester 72. 5-Benzyloxyisothiazole 70 was trans- S R2R3NH, r.t. 77 Et2O N formed into 5-hydroxy-4-chloro-3-trichloromethylisothi- Cl S azole (73) in preparative yields by the action of hydrogen in 80 (80–89%) the presence of palladium on carbon (A) or by treatment

Scheme 34 Synthesis of amides and esters of 4,5-dichloroisothiazole- with trifluoroacetic acid (B). 3-carboxylic acid The reactions of 4,5-dichloroisothiazole-3-carboxylic acid (74), synthesized from 4,5-dichloro-3-trichlorome- Aryl ketones 81a–c were synthesized through the thylisothiazole (66),32 with S,N-nucleophiles have been Friedel–Crafts acylation reaction using acid chloride 77 studied. Reactions with thiols were carried out in diethyl (Scheme 35).82 (4,5-Dichloroisothiazol-3-yl)ferrocenyl- ether in the presence of pyridine, which resulted in 5-al- ketone was also prepared in a similar manner.83 kyl(phenyl)sulfanyl-4-chloroisothiazole-3-carboxylic acids 75a–c in yields of 52–65% (Scheme 32).76 O O Cl Cl 1 R ONa, 60 °C, 10 h Cl Me Cl CO2H Cl CO2H Py, RSH 75a: R = n-Bu N 1 Cl 77 R OH 75b: R = Bn S R1O N N Et2O N S Cl RS 75c: R = Ph 1 S S 1. ArH, AlCl3, CH2Cl2 82a: R = Me (85%) 74 75a–c reflux, 2 h, 82b: R1 = Et (70%) 2. aq HCl Scheme 32 Nucleophilic substitution in 4,5-dichloroisothiazole-3- O R2SH, MeONa O carboxylic acid Cl for 81b 50 °C, 15 h Cl Me R R = 4-Me MeOH N 2 N Cl S R S S 2 Subsequently, 4,5-dichloroisothiazole-3-carboxylic acid 81a: R = H (86%) 83a: R = Bu (50%) 81b: R = 4-Me (72%) 83b: R2 = Ph (60%) tert-butyl ester 76, obtained from acid chloride 77, was 81c: R = 2,5-2Me (63%) used to study the possibility of carrying out reactions with , reflux, 12 h O N Cl Me N-nucleophiles (Scheme 33). The possibility of promoting H EtOH N the nucleophilic substitution of the chlorine atom at the 5- N S position of the heterocycle with amines in the presence of 84 (85%) fluorine ions was demonstrated.78 The yield of the corre- Scheme 35 Preparation of 3-ketoderevatives of 4,5-dichloroisothiazole sponding 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 NH > XNH>>RNH2 RNHCH3 > RNHR the amine added to the reaction. ( )n The reactivity of amines in the nucleophilic substitution n = 1, 2 X = NH, O of the chlorine atom at position 5 decreases in the series Figure 1 shown in Figure 1.

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Reactions with O-, N- and S-nucleophiles were investi- O O 1. Br2, NaOH, 0 °C NH gated using ketone 81b. The reactions of this ketone with Cl Cl 3 Cl NH2 2. 95 °C H O O-nucleophiles – sodium alkoxides – in a medium of the N N 2 Cl S Cl S corresponding alcohol at 60 °C resulted in alkoxy deriva- 77 85 tives 82a and 82b, while reactions with S-nucleophiles – 78% NaN3, H2O sodium thiolates, generated in situ in anhydrous methanol, Me2CO led to the corresponding sulfides 83a and 83b. The reaction O reflux aq HCl Cl NCO Cl NH2 with piperidine, as an example of an N-nucleophile, was Cl N3 20 min reflux, 1 h PhH N PhH N carried out in ethanol with a double excess of piperidine, N Cl S Cl S Cl S 80% and the yield of the corresponding 5-piperidinyl derivative 86 (79%) 87 84 was 85% (Scheme 35). O 92% Some of the synthesized isothiazole-containing amides, Cl HN reflux KOH esters, and ketones were able to exhibit potentiating activi- OEt EtOH N ty in compositions with the insecticides imidacloprid Cl S and/or -cypermethrin, with larvae of the Colorado potato 88 (94%) beetle.84–87 Some derivatives with fungicidal activity were Scheme 36 Pathways to the synthesis of 3-amino-4,5-dichloroisothi- also found.88 In the case of -cypermethrin, when used in a azole composition with an insecticide, the maximum synergistic effect was achieved by using a 4,5-dichloroisothiazole de- whilst the reaction with piperidine in methanol led to the rivative with 5–10% of the active component of the insecti- formation of 5-piperidinyl-substituted isothiazole 91. Reac- cidal composition.89 tions with thiolates using benzylmercaptan and thiophenol Based on 4,5-dichloroisothiazole-3-carboxylic acid am- as thiols proceeded in methanol with satisfactory yields, ide (85) and azide 86, both obtained from 4,5-dichloroiso- with the formation of derivatives 92a and 92b, respectively. thiazole-3-carboxylic acid chloride (77), 3-amino-4,5-di- When n-butylmercaptan was used, a mixture of the thiobu- chloroisothiazole (87) was synthesized by the Hoffmann tyl derivative 93a and the product of its alcoholysis 93b was and Curtius reactions.90 It was possible to achieve a 92% formed. In isopropyl alcohol, the yield of isothiazole 93a amine yield via the preliminary in situ preparation of ethyl was 68%. carbamate 88, which was then subjected to alkaline hydro- The possibility of further transformation of the nitrile lysis (Scheme 36). group was illustrated by synthesizing disubstituted 1,2,4- 4,5-Dichloroisothiazole-3-carboxylic acid nitrile (89) oxadiazoles 94 after obtaining the 4,5-dichloroisothiazole- was synthesized by the action of phosphorus pentoxide on 3-carboxylic acid amidoxime 95, and its subsequent acyla- 4,5-dichloroisothiazole-3-carboxylic acid amide (85), both tion and cyclization (Scheme 38).92 without solvent and in tetrachlorethylene. In both cases, The yields of acylamidoximes 96 were 85–95% for all de- the target nitrile was obtained in a quantitative yield.91 Sub- rivatives, except for the case when the acylation was carried sequently, reactions of the synthesized nitrile with O-, N- out with trichlorovinylacetic acid, for which the yield of the and S-nucleophiles were studied (Scheme 37). corresponding acylamidoxime was 71%. Method B provided The reaction with O-nucleophilic sodium methoxide led slightly higher yields of the target acylamidoximes com- to the formation of a mixture of 5-methoxy-4-chloro-3-cy- pared with method A. The acylamidoximes were further anoisothiazole (90a) and the product of its alcoholysis 90b, cyclized in the presence of acetic acid at reflux in yields of

Cl NH2 Cl CN R2SH, MeONa

Cl N MeOH 2 N Cl R1 S R S S MeONa 85 92a: R2 = Bn (64%) MeOH 2 N P2O5 92b: R = Ph (67%) MeO S 90a: R1 = CN + Cl CN Cl R1 n-BuSH, MeONa 90b: R1 = (C=NH)OMe N MeOH N Cl S n-BuS S Cl CN 1 N 89 (95%) 93a: R = CN + H 93b: R1 = (C=NH)OMe N N MeOH S Cl CN n-BuSH, i-PrONa 91 (53%) i-PrOH N n-BuS S 93a (68%)

Scheme 37 Synthesis and modifications of 4,5-dichloroisothiazole-3-carboxylic acid nitrile

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R dine) were more active. In a DMSO solution at 70 °C, HN O Cl CN nucleophilic substitution of the chlorine atom at position 5 H2N NH2OH Cl NHOH A: RCOCl, Et3N, Et2O O Cl N of the heterocycle was complete within 5 hours, with good N EtOH B: (RCO) O, DMAP, Et O Cl S N 2 2 Cl S yields being obtained. The ketones 97b and 98a were fur- Cl N S ther reduced to secondary alcohols 99a and 99b by the ac- 89 95 96 (71–95%) Cl tion of sodium borohydride in isopropanol (Scheme 40). N R = Me, i-Pr, Ph, CH2-CCl=CCl2 Cl O reflux In addition, the reactions of (4,5-dichloroisothiazol-3- 4,5-dichlorothiazol-3-yl AcOH S N N R yl) methyl ketone (97b) with elemental bromine in carbon 94 (90–92%) tetrachloride and anhydrous acetic acid were studied Scheme 38 Transformation of the nitrile group in 3-cyano-4,5-di- (Scheme 41). Bromination in these two solvents proceeded chloroisothiazole to 1,2,4-oxadiazole ring with significant tar formation, leading to bromomethyl(4,5- dichloroisothiazol-3-yl) ketone 100 in yields of 32% and 90–92% (Scheme 38). In the case of pivaloylamidoxime, the 46%, respectively. Substitution of two hydrogen atoms in heterocyclization did not proceed under the proposed con- the methyl group for bromine atoms was not observed. The ditions, presumably due to steric hindrance. reaction in carbon tetrachloride was complete in 2 hours, Nitrile 89 was successfully used as a starting material whilst the bromination in acetic acid was complete in 1 for the synthesis of isothiazole-containing alkyl ketones hour. It was noted that replacement of the solvent with 97a and 97b by addition reactions with alkylmagnesium chloroform or dichloromethane did not lead to positive re- halides (Scheme 39).93 sults; in both cases, the bromination did not proceed. The reaction of bromoketone 100 with thiourea in an ethanol O solution at 60 °C proceeded smoothly over 3 hours and re- Cl CN Cl R 1. RMgX, Et2O sulted in 2-amino-4-(4,5-dichloroisothiazol-3-yl)thiazole + N 2. H2O, H N Cl S Cl S (101) in a yield of 82%. 89 97a: X = Br, R = Et (70%) 97b: X = I, R = Me (80%) O Br2, CCl4 O Br Cl Cl Me 32% Cl (NH ) C=S NH Scheme 39 Preparation of 3-alkylketo-4,5-dichloroisothiazoles 2 2 Cl N 2 EtOH N Br2, AcOH Cl N S S Cl S S N 46% 97b 100 101 (82%) The possibility of using alkyl (4,5-dichloroisothiazol-3- yl)ketones for the synthesis of functionally substituted iso- Scheme 41 Modification of the acyl substituent in (4,5-dichloroisothiazol-3-yl) methyl ketone thiazoles through replacement of the chlorine at position 5 of the heterocycle and the transformation of alkylcarbonyl The synthesis of novel isothiazolyl-cymantrene deriva- fragment was evaluated with (4,5-dichloroisothiazol-3-yl) tives of 1H-pyrazole-1-carboxamide 102, dihydroisoxazole methyl ketone (97b) as an example (Scheme 40).93 103 and 1H-pyrazole-1-carbothioamide 104 was reported on the basis of the transformation of cymantrenyl chalcone O HO 105, obtained through condensation of aldehyde 106 and O Cl Me NaBH R1R2NH 4 Cl 95 Cl Me r.t., 48 h Me acetylcymantrene (Scheme 42). DMSO R1R2N N i-PrOH S 1 2 N Cl N R R N S S 97b 98a (80%), 98b (85%) O 99b (86%) O Me O HO KOH Cl N N Cl Cl Me 1 2 + NaBH R R N = (98a, 99b) (98b) i-PrOH Mn 4 N Mn r.t., 48 h O Cl N OC CO Cl N Cl S OC CO S OC S OC i-PrOH 99a (87%) 106 107 105 (59%) Scheme 40 Some transformations of 3-acetyl-4,5-dichloroisothiazole O S H NOH HN 2 HN t-BuOH • HCl t-BuOH t-BuOH NH H2N 2 H2N NH2 First, reactions with amines were investigated. It had • HCl Cl been previously shown that the reaction of (4,5-di- Cl Cl Cl S chloroisothiazol-3-yl) phenyl ketone with amines proceed- Cl Mn CO Cl N Mn N OC CO CO ed with substitution of the chlorine atom at position 5 of S N S N N N N N O OC CO S Mn the heterocycle by the amine residue. In aprotic bipolar sol- O OC CO NH NH2 OC vents (N-methylpyrrolidone and DMSO) at 130–140 °C, the 2 102 (79%) 103 (68%) 104 (82%) process was complete in 6 hours.94 Compared to (4,5-dichloroisothiazol-3-yl)(4-methylphenyl) ketone, the reac- Scheme 42 Synthesis and transformations of cymantrenyl substituted tions of ketone 97b with amines (morpholine and piperi- isothiazoles

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Cl Cl S Cl Cl

H2N NH2 S S N M CO + N KOH, t-BuOH M CO HN NH HN N O OC CO OC CO Cl S S 108a (84%) 108b Mn OC Cl Cl N CO NH Cl S OC 105 H N NH S 2 2 N M KOH, t-BuOH NN CO OC CO NH2 109 (67%)

Scheme 43 Construction of polynuclear derivatives of isothiazole

The reaction of chalcone 105 with thiourea allowed 3,4- 4 Selected Synthesis of Biologically Active dihydro- and 5,6-dihydropyrimidine-2(1H)thiones 108a Isothiazole Derivatives and 108b to be obtained in an overall yield of 84%, and the reaction with guanidine hydrochloride afforded 2-amino- As already mentioned, compounds containing an isothi- pyrimidine derivative 109 (Scheme 43). azole fragment have a broad spectrum of biological activity, Reaction of aldehyde 106 with 1,1′-diacetylferrocene including pesticidal, anticancer, antimicrobial, and antivi- (110) allowed 3-(4,5-dichloroisothiazol-3-yl)[5]ferroceno- ral. The mechanism of the biological action of these com- phane-1,5-dione 111 to be obtained (Scheme 44).83 pounds has only been studied for some of their representatives. O For example, compound 115 (Figure 2) is a vascular en- O Cl O Me Cl dothelium growth factor receptor inhibitor (VEGFR-2) of Cl KOH

+ Fe tyrosine kinase, and it has been proposed as an anticancer O DMF, i-PrOH N S Cl N Fe S therapy drug that prevents the growth and metastasis of Me O tumors.97 Although being an inhibitor of a protein signifi- 106 110 111 (65%) cant for the treatment of cancer diseases, a reinforcing ef- Scheme 44 Design of ferrocenyl containing isothiazoles fect was not observed during clinical trials in combination with known antitumor drugs.98 Isothiazole-modified nucle- The conversion of various isothiazoles 112 into pyra- oside 116 (Figure 2) is effective against the first type of her- zoles on treatment with hydrazine was investigated. The in- pes virus (HSV-1), and the interaction mechanism involves fluence of various C-3, C-4 and C-5 isothiazole substituents its binding to thymidine kinase HSV-1.99 and some limitations of this ring transformation were ex- 96 Br N S amined in detail. It was found, that when the isothiazole H N O C-3 substituent was a good nucleofuge, 3-aminopyrazoles F 113 were obtained. However, when the 3-substituent was HO NH Cl O F O not a leaving group it was retained in the pyrazole product N O N N 114 (Scheme 45). H N S H OH

115 116 1 1 R1 R R NH2 R R NH2NH2 + Figure 2 Examples of biologically active isothiazoles for which the 2 N 2 N R2 N R N R N mechanism of biological activity has been proposed S H H 112113 114 up to 100% depending on the nature of the Recently, it has been shown that the isothiazole nuclei R = Cl, Br, I, OMe, OH, NH2, substituents NHBn, N-morpholino of a number of derivatives can interact with target biomole- 1 R = CN, H, Br, Ph, NH2 cules, not only through van der Waals interactions and hy- 2 R = aryl, N-morpholino, NH2, NHNH2, drogen bonds,100,101 but also by covalent binding at the un- NHPh, NHBn, OMe, OPh, SPh, Cl substituted position 4 of the heterocycle as a result of bio- Scheme 45 Conversion of isothiazoles into aminopyrazoles activation.102 This is an important factor that must be considered when designing and synthesizing new biologically active compounds containing an isothiazole heterocycle.

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The available literature data on the synthesis of biologi- during initial research and bio-testing, and if necessary (for cally active isothiazoles includes not only information example, when the desired biological activity is detected), about the relationships between the structures of com- further optimization of the procedure can be carried out. pounds and their biological activities, but also important Another example of this strategy is the formation of information on the approaches used in multistep targeted substituted isothiazoles via the transformation of other syntheses of isothiazole-containing molecules. Considering functionalized heterocycles such as isoxazoles. Thus, in the the target functionalization of isothiazoles, it seems appro- synthesis of cyclooxygenase inhibitor 1 (COX-1) analogues, priate to pay attention not only to individual methods of isothiazole derivative 122 was obtained starting from isox- isothiazole heterocycle formation and ways of modification, azole inhibitor 123 through reductive opening of the isox- but also to synthetic strategies and approaches used in mul- azole ring with hydrogen in the presence of Raney nickel, tistage syntheses of target isothiazoles. As examples of such followed by cyclization of the resulting enamine ketone 124 strategies and approaches, the synthetic schemes toward by the action of phosphorus pentasulfide in the presence of some biologically active isothiazoles appear particularly chloranil (Scheme 47).103 useful and informative. At the same time, attention will be paid to the stages that include the formation or involve- Cl Cl Cl H2, Raney Ni chloranil Ph O Ph O Ph O ment of the isothiazole heterocycle in chemical transforma- 20 °C, 16 h P2S5, reflux EtOH PhMe tions. Me N Me NH2 Me N O O S We can identify three rather conventional strategies for 123 124 (71%) 122 (45%) the targeted production of biologically active isothiazoles: (1) Introduction of the isothiazole fragment at the final Scheme 47 Synthesis of cyclooxygenase inhibitor 1 (COX-1) analogues with the fragment of isothiazole stage. (2) Convergent synthesis of functionalized isothiazoles. (3) Multistage synthesis based on the isothiazole nucle- This method has several disadvantages; however, the us. yield of the corresponding enamine ketones (38–90%) As an example of the first strategy, we can cite the final strongly depends on the substituents present on the isoxaz- stages of the synthesis of nucleoside 116 (Scheme 46).99 ole ring, and their cyclization into isothiazoles usually pro- 3′,5′-Di-O-acetyl-2-deoxy-5-iodouridine 117 was intro- ceeds with rather low yields (21–51%).104 Regardless, this duced into the Sonogashira reaction with 3,3-diethoxy- pathway can be useful in the synthesis of promising biolog- prop-1-yne (118) and subsequent hydrolysis of the ob- ically active compound libraries for biological screening, tained alkyne derivative 119 gave aldehyde 120. This in subject to the availability of the corresponding substitute turn was reacted with sodium thiosulfate and the resulting isoxazoles. thiosulfate derivative 121 was treated with liquid ammonia The strategy associated with the convergent synthesis without purification to give nucleoside 116. of isothiazoles, including demonstrating the potential of isothiazole halogen derivatives in preparative organic syn- OEt O thesis, was used in the final stage of the preparation of a se- O I EtO NH [PdCl ((Ph) P) ] lective inhibitor of the metabotropic glutamate receptor 5 OEt 2 3 2 NH CuI, 50 °C (mGluR5) 125 (Scheme 48).105,106 3,4-Dibromisothiazole AcO N O + O EtO N O Et3N AcO O amide 126 was introduced into a Suzuki cross-coupling reaction with boric acid pinacol ester 127. The product 128 OAc OAc thus obtained was then subjected to a Stille reaction with 117 118 119 (91%) the pyridine organotin derivative 129 to deliver the target aq AcOH product 125. NaO S O N S O 3 Perhaps the most common strategy is sequential multi- O S O O NH Na S O step synthesis based on the isothiazole core with reactive NH3 NH 2 2 3 NH –70 °C 0 °C HO N O substituents. This method is used in the synthesis of a O AcO N O N O O H2O AcO O number of substituted 2-(isothiazol-3-yl)-1,3,4-oxadiazoles Me2CO AcOH 130 possessing significant antimitogenic activity, achieved OH OAc OAc through the depolymerization of microtubules (Scheme 116 (13%) 121 120 (51%) 49).107 Scheme 46 Synthesis of a nucleoside bearing an isothiazole ring Hydrazide 131, obtained from 4-aminoisothiazole-3- carboxylic acid amide (132), was further reacted with aryl In this example, the formation of the isothiazole ring is a isothiocyanates. The substituted acylsemicarbazides thus factor limiting the yield of the target nucleoside 116. How- synthesized were transformed by the action of N,N′-dicy- ever, low yields of the target products can be justified clohexylcarbodiimide (DCC) into 1,2,4-oxadiazoles 133, which were subjected to reductive amino group alkylation.

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shown that 4,5-dichloroisothiazole-3-carboxylic acid vanil- O lin ester exhibits potentiating activity in a composition B O Me N N with the pyrethroid insecticide cypermethrin, and its Br Br NMe N 127 azomethine and amine derivatives possess potentiating ac- N [PdCl2(PPh3)2] Br HN S tivity when combined with the neonicotinoid insecticide 2 M Na2CO3 (aq), 80 °C 85,108 O N imidacloprid. The effect was observed when testing the glyme HN S Me corresponding insecticidal compositions on Colorado pota- 126 O 128 (50%) to beetle larvae. In order to clarify the effect of structural Me N and functional changes in the molecules of the vanillin iso- MeN thiazole derivatives on their biological activity, an isovanil- i-Pr 129 N Bu3Sn N i-Pr lin analogue of the isothiazole vanillinate was synthesized, N as well as 5-alkyl(aryl)thio-substituted 4-chloroisothiazoles S NH 1. (t-Bu3P)2Pd, glyme, 100 °C 2. HCl, Et2O containing the vanillin moiety (Scheme 50).109 An opti- O 125 (65%) mized method was used for producing 5-butyl(benzyl, phe- Me nyl)thio-4-chloroisothiazole-3-carboxylic acids 75a–c. The Scheme 48 A selective inhibitor of the metabotropic glutamate recep- methyl ester of 4,5-dichloroisothiazole-3-carboxylic acid tor 5 (mGluR5) with the isothiazole central nucleus 135 was treated in situ with the corresponding sodium thi- An alternative method for the synthesis of the desired iso- olates in anhydrous methanol, followed by hydrolysis of the thiazol-3-yl-oxadiazoles consisted of the initial reductive intermediate methyl-5-alkyl(benzyl, phenyl)thio-4- alkylation of compound 132, transformation of the amide chloroisothiazole-3-carboxylates 136. The synthesis of van- groups of the resulting compounds 134 into hydrazide illin esters 137a–c was carried out by the acylation of vanil- groups, subsequent formation of semicarbazides, and then lin with 5-butyl (benzyl, phenyl)thio-4-chloroisothiazole- formation of the 1,3,4-oxadiazole fragments. 3-carbonyl chlorides 138a–c, which were obtained by boil- A series of vanillin-containing isothiazole derivatives ing the acids 75a–c with thionyl chloride in the presence of was synthesized by successive transformations of the sub- a catalytic amount of DMF. stituents on the isothiazole nucleus. It has previously been

1 N H O O NH2 1. Ar -NCS, t-BuOH N N Ar1 H2N NH2 N2H4·H2O H2N NH reflux H2N O reflux N N 2. DCC, MeCN, reflux S S N S 132 131 (70%) 133 (56–80%)

1. Ar2CHO, MeCN 1. Ar2CHO, MeCN p-TsOH, reflux p-TsOH, reflux 2. NaBH , i-PrOH, reflux 4 H 2. NaBH , i-PrOH O N N 4 N 1 1. N2H4·H2O, reflux Ar reflux NH NH2 2 NH O Ar 2 N 2. Ar1-NCS, t-BuOH, reflux Ar S N 3. DCC, CH3CN, reflux S 134 (59%) 130 (75–88%) Scheme 49 Synthesis of isothiazol-3-yl-oxadiazoles possessing antimitogenic activity

Cl CO2Me 1. KOH Cl CO H Cl CO2H 1 2 Cl COCl R SNa H2O SOCl2 1 N + N MeOH R S S 2. H R1S N R1S N Cl S S S 74 136 75a–c (82–95%) 138a–c

Cl CO2Me OH MeOH OMe a: R1 = n-Bu; b: Bn; c: Ph; R2 = 4-MeC H H+ N 6 4 Et2O, Et3N Cl S 135 O Cl Cl Cl 1 2 1 2 2 1 R S O R R S O R R NH2 R S O NaBH NH 4 N H+ (cat.) O S S S N O N O N O AcOH MeOH MeO MeO MeO 140a–c (85–93%) 139a–c (78–92%) 137a–c (85–92%)

Scheme 50 Synthesis of isothiazolic esters of vanillin and their azomethines

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Azomethines 139a–c were obtained by condensation of Cl esters 137a–c with p-toluidine in dry methanol, with yields Cl S Cl OH of 78–92%. Compounds 139a–c were further reduced to the N N N Me corresponding amines 140a–c with high yields by the ac- Cl S O tion of sodium borohydride and acetic acid in benzene. 143MeO 142 (72%) Vanillin ether 141, containing a 4,5-dichloroisothiazole CCl4 MeOH Me NH2 moiety, and also azomethine 142 based on it, were pre- SOCl2 AcOH (cat.) pared in order to study the effect of the nature of the linker MeO Cl O between the isothiazole and vanillin fragments on the bio- Cl S Cl Cl HO logical activity of vanillin derivatives of isothiazole (Scheme N O 110 Cl N NaH, DMF 51). (4,5-Dichloroisothiazol-3-yl) carbinol 143 was react- S O ed with thionyl chloride in carbon tetrachloride to form 144 (66%) 141 (71%) MeO (4,5-dichloroisothiazol-3-yl) chloromethane 144 in a satis- Scheme 51 Synthesis of isothiazolic ether of vanillin and its azo- factory yield. Alkylation of vanillin with chloromethane 144 methine in dimethylformamide using sodium hydride as the base led to the formation of vanillin ether 141 in a 71% yield. The compound 150. After deprotection of the pyrazole nitrogen resulting ether was introduced into a condensation reaction by the action of hydrochloric acid in dioxane, the desired with p-toluidine in methanol in the presence of a catalytic inhibitor 151 was obtained. amount of acetic acid to form azomethine 142 (Scheme 51). Finally, using this strategy, a collection of 4-chloroiso- Isothiazolic derivatives of comenic acid were prepared in a thiazole-containing carbamides113,114 and amides,115 as vas- similar manner.111 cular endothelium growth factor receptor inhibitor (VEGFR- Another example of such a strategy is the synthesis of 2) 115 analogues (see Figure 2), was synthesized for bio- the Aurora kinase inhibitor, serine/threonine kinase, which testing in compositions with known antitumor drugs. Some plays a crucial role in cell proliferation (Scheme 52).112 of the obtained compounds were able to potentiate activity Methyl ether 145 was reacted with intermediate 146 in the of the known anticancer drugs cisplatin, cytarabine, and presence of sodium hydride, and the carboxyl group in the etoposide in vitro.113 obtained product 147 was reduced by lithium triethylboro- The approach chosen for the synthesis of isothiazole- hydride in tetrahydrofuran. The resulting alcohol 148 was containing carbamides included the initial preparation of then mesitylated to form ester 149. Transformation of the the corresponding (isothiazol-3-yl)carbonyl azides 86 and ester group into a tertiary amino group by reaction with 2- 152. To obtain 5-benzylthio-4-chloroisothiazole-3-carbonyl (ethylamino)-2-methylpropan-1-ol led to the formation of azide (152), two approaches were tested: using acid chloride 138b and 5-benzylthio-4-chloroisothiazole-3-carbox-

N N H SO Me CO Me N CO Me N 2 2 2 N NaH N N + S N N N N N H N N DMF SEM 2 S SEM Me Me 146145 147 (86%)

LiBH(Et)3 25 °C, THF

N H OMs N H N MsCl, Et3N N N N 25 °C N N OH S N S N N N THF N N SEM SEM Me Me 149 (83%) 148 (85%)

R1R2NH (150), NaI,

80 °C, N2, 8 h THF 1 2 1 2 NR R N H NR R N HN N N 80 °C, 20 min S N N N N S N 4 N HCl N N N ·HCl dioxane SEM N Me Me H 150 (60%) 151 (90%) Me 1 2 Me SEM = O R R NH = HN SiMe3 Et OH Scheme 52 Synthesis of Aurora kinase inhibitor

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with urethanes 154a and 154b were carried out in aqueous O Cl CO2H Cl COCl 115 SOCl2 NaN3 Cl N3 ethanol. The obtained carbamides 156 were then trans-

N N Me2CO, H2O formed into the corresponding salt forms 157 by treatment Cl S Cl S N Cl S with sodium carbonate (Scheme 55). 74 MeOH 77 86 The amide synthesis involved the acylation of selected O Cl CO Me amino acids with 4,5-dichloroisothiazole-3-carboxylic acid Cl CO2Me 2 Cl BnSH, MeONa NH2NH2 NHNH2 azide 86 in methanol, followed by conversion of the synthe- N MeOH N MeOH Cl BnS S N sized amides 158 into their salt forms 159 by reaction with S BnS S 135136b (97%) 153 (95%) sodium bicarbonate (Scheme 56). NaNO Et O 1. KOH, H2O 2 2 Among biologically active isothiazoles, benz[d]isothi- HCl H O 2. H+ 2 azoles occupy an important place. The benz[d]isothiazole O O Cl CO2H moiety has been successfully used in the design and syn- SOCl Cl Cl NaN Cl N3 2 3 thesis of neuroleptic ziprasidone as well as in the synthesis N Me2CO, H2O BnS S N N BnS S BnS S of a number of ureas and thioureas, which showed both in 75b (95%) 138b (95%) 152 (82%, vitro antiglycosylation activity and the ability to inhibit from 138b) urease.116 Some ureas and thioureas containing ben- Scheme 53 Approaches to the synthesis of 4-chloroisothiazole- zo[d]isothiazole fragments show high inhibitory activity containing azides against Mycobacterium tuberculosis GyrB DNA gyrase.117 In this regard, it is necessary to mention the recently pro- ylic acid hydrazide (153). Treatment of hydrazide 153 with posed original approach to the synthesis of substituted nitrous acid (a mixture of NaNO2 and HCl) resulted in the benz[d]isothiazoles based on the Diels–Alder reaction, target 5-benzylthio-4-chloroisothiazole-3-carboxylic acid which has been successfully demonstrated with the exam- azide (152). However, due to the low solubility of hydrazide ple of 3-phenyl-4,5-bis(carbomethoxy)isothiazole (160) as 153 under the reaction conditions, the process proceeded the starting compound (Scheme 57).118 slowly and the yield of azide 153 did not exceed 65%, The carboxyl groups of isothiazole 160 were trans- whereas the reaction of 5-benzylthio-4-chloroisothiazole- formed into carbinols by the action of borohydride in an carbonyl chloride (138b) and NaN3 gave the target azide ethanol/tetrahydrofuran medium, forming the diol 161. 152 in a yield of 82% (Scheme 53). The carbinol groups of diol 161 were further converted into The hydrazide 153 was synthesized in a 95% yield by the bromomethyls by reaction with phosphorus tribromide action of hydrazine hydrate on ester 136b in methanol. and pyridine in dichloromethane. The reaction of the Subsequently, azides 86 and 152 were used to synthesize carbamates, as immediate precursors of ureas (Scheme 54). O OH Cl Cl O The synthesized isothiazolylcarbamates 154a and 154b H n H H N O H2N N N R R n OH were further reacted with aliphatic amines, including func- EtOH, H O N O 2 N O tionalized examples (n-hexylamine, 6-aminohexanol, 2- S X S n = 1, 3 aminoethoxyethanol, N′,N′-dimethylpropan-1,3-diamine). 154a,b 156 (89–94%) O In addition to the p-fluorophenol carbamate, ethyl carba- Cl H H N N NaHCO3 R n ONa mate 155 was obtained from azide 152; it had greater solu- MeOH, H2O S N O bility but did not react with amines under the utilized con- R = BnS (154a), Cl (154b) 157 (98–99%) ditions, even with prolonged boiling of the reaction mix- X = F (154a), H (154b) ture. In the case of -aminobutyric and -aminocaproic Scheme 55 Preparation of isothiazolic ureas on the basis -amino- acids, which are poorly soluble in chloroform, the reactions butyric and -aminocaproic acids

X OH O 2 Cl HN X R NH2

PhH O CHCl3 N 2 R S HN R N3 Cl HN 154a: X = F Cl O O 154b: X = H R N N S R S OEt 156 (83–95%) 86, 2 reflux Cl HN R NH2 152 R = BnS (154a), Cl (154b) O EtOH R2 = alkyl N CHCl3 BnS S 155 Scheme 54 Synthesis and modification of isothiazolylcarbamates

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O O () O O H2N n O Cl Cl NaHCO3 Cl N3 OH NH () () n O N n ONa H MeOH MeOH, H2O N N HO Cl N Cl S Cl S S 86 158 (86–89%) 159 (98%) Scheme 56 Synthesis of 4,5-dichloroisothiazolic amides of -aminobutyric and -aminocaproic acids, n = 1, 3 (yield is 98% in both cases)

The formation of by-products 169 was observed during O MeO Ph HO Ph Br Ph the formylation stage of the reaction, and so the imines 168 NaBH4, EtOH PBr3, Py MeO HO Br together with impurities were introduced into the oxida- N THF N CH2Cl2 N S S S tion reaction with iodine, and the impurities were removed O 160 161 (75%) 162 (55%) during purification of the target products 166. NaI DMF An alternative strategy was proposed for the synthesis O O Ph of brassilexin (166a) through the formylation of indolin-2- MeO Ph [O] MeO Ph DMAD MeO one (170), followed by heterocyclization of the resulting 2- MeO – 2H N N N S bromo-1H-indole-3-carbaldehyde (171) in a reaction with O S O S 165 (48%) 164 163 urea and sodium thiocyanate under microwave irradiation 120 Scheme 57 A promising approach towards substituted benz[d]isothi- (Scheme 59). This strategy has also been successfully ap- azole plied in the synthesis of isothiazole-containing steroids.120

O N O PBr3, DMF, CHCl3 (NH2)2C=O, NaSCN S resulting 4,5-bis(bromomethyl)-3-phenylisothiazole (162) Br N 60–70 °C, 5 h DMF, MW H N N with sodium iodide in dimethylformamide led to the gener- H 140 °C, 10 bar, 3 min H ation of the highly active diene 163, which was immediate- 170 171 (70%) 166a (82%) ly reacted with dimethyl acetylenedicarboxylate (DMAD). Scheme 59 An alternative way for the synthesis of fungicide brassilexin 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 Isothiazoles condensed with pyrazole rings were found substituted benz[d]isothiazoles, and is expected to find fu- to be promising biologically active compounds with fungi- ture applications in the synthesis of many biologically ac- cidal properties.121,122 For their synthesis, a strategy has tive derivatives of benz[d]isothiazole. been reported consisting of the oxidation of 1-aryl-5-ami- As an example of other methods for condensed isothi- no-3-methylpyrazole-4-carboxylic acid thioamides 172 azole derivatives, we should cite the synthesis of the fungi- with hydrogen peroxide in pyridine, leading to good yields cide phytoalexin brassilexin along with its analogues 166, of the desired 3-aminopyrazolo[3,4-c]isothiazoles 173 which also exhibit antifungal activity and contain the iso- (Scheme 60). In this case, nitrile 174 was formed in trace thiazole cycle. One of the proposed strategies for the syn- amounts. At the same time, the use of iodine as an oxidizing thesis of these compounds is the Vilsmeier formylation of agent in a tetrahydrofuran medium resulted in the forma- substituted indolin-2-thiones 167, followed by treatment tion of either only product 174 or a mixture of products with aqueous ammonia and oxidation of the extracted with a predominance of the 4-cyano derivative 174 in a ra- imines 168 with iodine in pyridine (Scheme 58).119 tio of 95:5. In the case of a 2,5-dichlorophenyl derivative, the corresponding nitrile was the main oxidation product. 1 NH R 1 Some of these synthesized 5-aminopyrazolo[3,4-c]isothi- 1. POCl3, DMF R S S azoles have been shown to be promising as safe antiderma- R2 N 2. NH3, NH4OH R R2 N 123 R tophytic drug candidates. 167 168 I Py 2 S NH 2 NC Me R1 Me R1 H2N Me 1 N H2O2, 0 °C S 2 R + N 2 R S N Py N N H2N N R + H2N N N R2 N R R R R N S N R R 172 173 174 169 166 (40–71%) R = Ph; 2-ClC6H4; 3-ClC6H4; 4-ClC6H5; 2,4-Cl2C6H3; 3,4-Cl2C6H3; 2,5-Cl2C6H3 R = H, Me, OMe Yield 173 84% 45% 72% 68% 50% 73% 20% R1 = Me, OMe, F, Cl, Br, H R = 3-O2NC6H4; 4-O2NC6H4; t-C4H9 Yield 173 75% 95% 35% R2 = Me, OMe, F, Cl, Br, H Scheme 58 Synthesis of brassilexin and its analogues Scheme 60 Oxidation of 5-aminopyrazole-4-carboxylic acid thioamides leading to 3-aminopyrazolo[3,4-c]isothiazole system

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The interaction of 5-aminopyrazoles 175 with Appel’s es are polymer structures, CoCl2L4 and CoBr2L4 are octahe- salt (176) represents another approach to the synthesis of dral, and CoI2L2 and CoI4L2 are tetrahedral, but in solution condensed heterocyclic systems (Scheme 61), and pyrazole all complexes are characterized by a tetrahedral structure. derivatives of 1,2,3-dithiazole 177 and substituted pyrazo- For the CoI4L2 complex, instability with regard to the action lo[3,4-c]isothiazole-3-carbonitriles 178 have been ob- of atmospheric oxygen and decomposition in nitromethane served,124 rather than pyrazolo[3,4-d]thiazole-3-carboni- solution with the formation of molecular iodine and the 125 triles as previously believed. CoI2L2 complex were observed. The [CoL6](ClO4)2 complex is assigned an octahedral structure, both in solid form and in CN 2 R2 2 S R nitromethane solution, with the perchlorate anion in the Cl Cl R S a or b S N outer sphere of the complex. Based on the electronic and IR N + + N H N + S CH Cl N N N 2 N N 2 2 N Cl N spectra, it was suggested that isothiazole is coordinated – S 1 1 Cl 1 R R R through a nitrogen atom.126 175 176 177 (7–57%) 178 (up to 92%) In the other paper published in 1971,127 the trans- R1 = H, Me, t-Bu, Bn, Ph 2 a: b: 1. HCl (gas); 2. Co(NCS)2L4 complex was obtained, to which the octahedral R = Me, Ph Me N Me Me N Me structure was also attributed as a result of magnetic sus- Scheme 61 Investigation of the reaction between 5-aminopyrazoles ceptibility data. The hypothesis of the trans-form of the and Appel's salt complex is suggested based on the reaction with ,′-dipyr-

idyl, leading to the formation of a Co(NCS)2(bipy)2 complex The yields of compounds 177 and 178 depend on the as a result of ligand exchange. The same paper describes the temperature, reaction time, acidity of the reaction mixture, synthesis of complexes CuCl2L2, CuBr2L2, Cu(NO3)2L2, + and substituents on the pyrazole ring. When substituted [LH ]2[CuOCH2CH3(NO3)3L2] (unstable), Cu(NO3)2L4, NiCl2L4,

1H-pyrazoles were introduced into the reaction, the main NiBr2L2, Ni(ClO4)2L6, and cis-PtCl2L2. The synthesized com- products were pyrazole derivatives of 1,2,3-dithiazole, re- plexes were characterized using IR spectroscopy, elemental gardless of the reaction conditions, and pyrazolo[3,4-d]iso- analysis, magnetic susceptibility, and powder X-ray diffrac- thiazole-3-carbonitriles did not form. This is particularly tion. For complexes of the MHal2L2 type [M = Cu(II), Co(II); interesting because from the corresponding pyrazole deriv- Hal = Cl, Br] and for NiBr2L2, a polymer octahedral structure atives of 1,2,3-dithiazole, it is possible to synthesize thi- with bridging halogen atoms and isothiazole in the trans azoles isomeric to isothiazoles 177 by thermolysis, which position was proposed, while complexes NiCl2L4, may be convenient in the process of synthesizing libraries Cu(NO3)2L4, Cu(NO3)2L2, and Ni(ClO4)2L6 were characterized of compounds for biological screening. as octahedral. For cis-PtCl2L2, a cis-planar configuration was proposed with coordination through the nitrogen atom of the cycle. Later, various cobalt and nickel complexes with 3- 5 Isothiazoles in the Synthesis of Transition- , 4- and 5-methylisothiazoles were studied in detail.128,129 It Metal Complexes and in Metal-Complex Ca- was also shown that 3-methylisothiazole was only able to talysis form tetrahedral complexes of the MeX2L2 type, which was associated with steric hindrance created by the methyl The properties manifested by metal complexes are group at position 3 of the heterocycle. The isothiazole nu- largely determined by the ligand environment of the metal, clei in all the synthesized complexes are coordinated which ensures the creation of a specific distribution of the through a nitrogen atom. electron density on the metal atom and the formation of a The same researchers obtained Pd(II), Pt(II), Rh(III), and spatial framework around it. Information about the metal Ir(III) complexes with isothiazole and 3-, 5-methylisothi- complexes of the isothiazole series is sparse and fragmen- azoles: PdX2L2 (X = Cl, Br; L = isothiazole, 3-methylisothi- tary, and techniques for their practical application have azole, 5-methylisothiazole), PtCl2L2 (L = isothiazole, 3-me- been studied only as isolated examples. thylisothiazole, 5-methylisothiazole), RhCl3L3 (L = isothi-

The first information regarding such metal complexes, azole, 3-methylisothiazole, 5-methylisothiazole), RhCl3L4 (L published in two articles in 1971, was devoted to the syn- = 5-methylisothiazole), IrCl3L3 (L = 3-methylisothiazole, 5- 130 thesis and study of the structure of Co(II), Ni(II), Cu(II) and methylisothiazole), and IrCl3L4 (L = isothiazole). The un- Pt(II) complexes with unsubstituted isothiazole as a li- substituted isothiazoles in the complexes are coordinated gand.126,127 via a sulfur atom, while 3-methylisothiazole is coordinated

For cobalt, complexes CoX2L2, CoX2L4 and [CoL6](ClO4)2 via a nitrogen atom. 5-Methylisothiazole was coordinated were obtained, where L is an unsubstituted isothiazole and through a nitrogen atom in the Pd(II) and Rh(III) complexes, X = Cl, Br, I.126 The characterizations of their structures was and in the Pt(II) and Ir(III) complexes through a sulfur atom. accomplished by using elemental analysis, diffuse reflec- The literature describes only one example of an isothi- tance spectroscopy, magnetic susceptibility, conductivity in azole-containing complex with PdCl2, the structure of solution, and IR spectroscopy. CoCl2L2 and CoBr2L2 complex- which was accurately determined by X-ray crystal structure

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Syn thesis A. V. Kletskov et al. Review analysis (Figure 3).131 In this complex, palladium had a pla- Data on isothiazole-containing carbonyl complexes of nar environment with trans-oriented benzo[d]isothiazole tungsten LxW(CO)6–x, molybdenum LMo(CO5), and chromi- ligands. um LxCr(CO)6–x (L is the isothiazole ligand; x = 1, 2), ob- As part of studying the ability of 1,2-azoles to form met- tained by ligand exchange from the hexacarbonyl of the al complexes, stability studies of isothiazole complexes corresponding metal and isothiazole, 4-methylisothiazole with cobalt(II), nickel(II), copper(II), zinc(II), and silver(I) or 5-methylisothiazole under ultraviolet irradiation, have were carried out by potentiometric and photocolorimetric been published.135,136 At the same time, depending on the methods.132 The stability of the complexes varies in the se- irradiation time of the reaction mixture, substitution of one ries of 1,2-azoles as follows: pyrazole > isothiazole > isoxaz- to two carbonyl fragments in the starting metal hexacar- ole. It was suggested that the higher stability of the isothi- bonyl has been observed. Based on IR spectra, it has been azole complexes in comparison with their isoxazole ana- established that the synthesized complexes have a C4v sym- logues could be explained by the possibility of additional - metry group, and based on mass spectrometric data for the bond formation between the isothiazole and the metal cat- fragmentation of LxW(CO)6–x and LxCr(CO)6-x complexes and ion due to the presence of an unoccupied d-orbital on the the starting isothiazole ligands, it has been found that in all sulfur atom in the heterocycle. cases, the coordination was achieved through the nitrogen The literature describes bimetallic tetraselenocyanate atom.136 This was also consistent with the 1H NMR data for complexes of cobalt(II), nickel(II), cadmium(II), and mercu- the synthesized complexes. An attempt was made to syn- ry(II), in which isothiazole, 4-methylisothiazole, and 4-ben- thesize the isothiazole -complex based on the triacetoni- 133,134 zylisothiazole act as ligands. Assumptions about the trile tricarbonyl complex of chromium [(CH3CN)3Cr(CO)3], structures of these complexes were made based on elemen- but an unstable product was separated with an L3Cr(CO)3 (L tal analysis, UV-VIS and IR spectroscopy, magnetic suscepti- = isothiazole) structure, according to IR spectroscopy da- bility, and the HSAB theory, wherein a single monomer ta.136 complex L2Ni(NCSe)2Hg(NCSe)2 (L= methylisothiazole, with Finally, some examples of isothiazole complexes, in selenocyanate acting as a bridging ligand) was separated, in which the metal is coordinated not only through ring het- which nickel was in an octahedral environment, probably eroatoms, but also through heteroatoms of exocyclic due to the axial coordination of the selenocyanate frag- groups, are known. Thus, diperchlorate isothiazole complex ments of the upper layers. All other bimetallic complexes of 179 was obtained by treatment of Δ-bis(ethylenedi- different composition are described as polymeric tetrahe- amine)threoninatocobalt(III) trifluoromethansulfonate 180 dral, where the selenocyanate acts as a bridging ligand, the with thionyl chloride in dimethylformamide, followed by N-terminus is coordinated on cobalt and nickel, and the Se- ion exchange chromatography. In this case, the isothiazole- terminus is coordinated on cadmium and mercury. Coordi- 3-carboxylic acid acts as a bidentate ligand, chelating cobalt nation of isothiazoles occurs in these cases via a nitrogen through the heterocyclic nitrogen atom and carboxyl group atom at the axial positions in the case of Ni(II) and Co(II), or (Scheme 62).137 through sulfur in the case of Cd(II) and Hg(II). Me S NH2 H2 NH2 H2N N 1. SOCl2, DMF H2N N 2+ OH – 2+ 2– Co 2 CF3SO3 Co 2 ClO4 2. ion-exchange H2N O H2N O NH2 O chromatography NH2 O 180 179 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 as- sumed 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. In order to obtain the isothiazole complexes, Meyer et al.138 synthesized isothiazoles containing exocyclic chelat- Figure 3 The structure of a single palladium complex of isothiazole as ing fragments. Thus, pyridine-containing azomethines confirmed by X-ray crystal structure analysis (reproduced with permis- 181a and 181b were prepared from 5-formyl-3-methyliso- 131 sion) thiazole (182) (Scheme 63).

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Syn thesis A. V. Kletskov et al. Review

N fungicidal properties against the phytopathogenic fungi Me NH 2 N Botrytis cinerea and Fusarium sp., completely inhibiting the n S N O Me N EtOH N development of the fungi at a concentration of 0.125%, ac- S n cording to biological tests. The Cu(L )Br complex, being 182 181a: n = 1 (88%) 2 2 181b: n = 2 (92%) added at a 5% amount relative to the neonicotinoid insecti- Scheme 63 Synthesis of ligands with isothiazolic and pyridinic cores cide imidacloprid, increases by almost 2 times the toxicity of the insecticide toward Colorado potato beetle larvae, which increases the effectiveness of the insecticide and re- In addition to this, sulfide 183 was synthesized via the duces its consumption.139 Complexes of 4,5-dichloroisothi- lithiation of 3,5-dimethylisothiazole (184) (Scheme 64). Al- azole-3-carboxylic acid ethanolamide with copper bromide so, 3-bromomethyl-5-methylisothiazole (185) was ob- and copper chloride were also obtained, and according to tained starting from 3,5-dimethylisothiazole (184) through XRD data, 4,5-dichloroisothiazol-N-(2-hydroxyethyl)-3- bromination of the methyl group at position 3. The intro- carboxamide was coordinated to copper(II) in a tridentate duction of isothiazole 185 into the reaction with N,N,N′,N′- manner. In the bidentate cyclic-type complex, it is coordi- tetraethyldiethylenetriamine led to the formation of amine nated on the nitrogen atom of the heterocycle and on the 186. exocyclic oxygen atom of the amide group with the formation of the five-membered metallocycle CuNCO, and also on Me 1. LDA the oxygen atom of the substituent hydroxy group, and all 2. ClCH2SCH3 SMe N THF N these bonds form polymer chains. The complex of 4,5-di- Me Me S S chloroisothiazole-N-(2-hydroxyethyl)-3-carboxamide with 184 183 (54%) copper(II) bromide (Figure 4) can enhance the action of the NBS, (BzO)2 (cat.) heating, 12 h, CCl4 insecticides cypermethrin and imidacloprid, and at the

NEt2 same time, copper bromide and the ligand separately did Br HN(CH2CH2NEt2)2 141 Et N not show any similar activity with insecticides. 3 N NEt2 N Me Et2O S N Me S 185 (38%) 186 (59%) Scheme 64 Preparation of 3-substituted isothiazoles from 3,5-dimethylisothiazole

Based on the synthesized isothiazoles, binuclear isothiazole-containing silver triflate complexes [LAgOSO2CF3]2 (L

= 181a, 181b, 183) and [LAg]2[O3SCF3]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 (nitro- Figure 4 The structure of a polymeric copper complex of 4,5-di- gen or sulfur). In the case of L = 181b, the silver coordina- chloroisothiazole-N-(2-hydroxyethyl)-3-carboxamide with copper(II) tion occurs exclusively on the exocyclic heteroatoms bromide (reproduced with permission).141 The structure of the polymer (through the nitrogen of the azomethine and pyridine frag- complex with copper chloride is similar. ments).

Metal complexes with Cu(II) were obtained based on In 2011, the Pd(II) complex of composition L2Pd (L = 4,5- 4,5-dichloroisothiazole-3-carboxylic acid, its amide, and dichloroisothiazole-carboxylate) was synthesized from 4,5- benzotriazolamide.27,139,140 Polymer complexes of copper dichloroisothiazole-3-carboxylic acid.26 It could not be ob-

[LCuCl2]n, LCuBr2 (L = 4,5-dichloroisothiazole-3-carboxylic tained in crystalline form, and therefore, to describe its acid amide), Cu(L)(BtaH)(H2O)2(NO3) (L = 4,5-dichloroiso- structure, quantum chemical modeling using the thiazole-3-carboxylic acid, BtaH = benzotriazole), and B3LYP1/MIDI(3d) level of theory was used. According to the

(L)(CuH2O)Cl·0.5H2O (L = 4,5-dichloroisothiazole-3-carbox- quantum chemical calculations, a flat-square structure was ylate) were synthesized. The complexes were characterized attributed to the complex; however, it was not possible to by X-ray crystal structure analysis. In these complexes, iso- establish exactly whether the isothiazole fragments in the thiazole ligands chelated a copper atom with a nitrogen complex were in cis- or trans-form due to the proximity of atom of the heterocycle and with an oxygen atom of an am- their calculated formation enthalpies. The complex showed ide or carboxyl group. The complex [Cu(L2)Cl2]n possesses catalytic activity in the Suzuki reaction: on addition of 0.1

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mol% of the complex, the reaction of 2,4-difluorophenylbo- O O NHR ronic acid with 5-bromosalicylic acid, carried out in water Cl Cl NH2NHR Cl NH Et N, Et O exposed to air at 100 °С, was complete in 15 minutes with a N 3 2 N Cl S Cl S quantitative yield of 5-(2,4-difluorophenyl)-2-hydroxyben- 77 187a: R = H (98%) zoic acid being obtained. The latter is active pharmaceutical 187b: R = Ph (78%) substance diflunisal, a nonsteroidal anti-inflammatory Scheme 65 Preparative synthesis of hydrazides of 4,5-dichloroisothi- drug (NSAID) with analgesic and antipyretic effects. azole-3-carboxylic acid The possibility of using isothiazole complexes with palladium(II) as a catalyst for cross-coupling reactions is of todeboronation) and 3-bromobenzoic acid (189). The target particular interest because of its relevance both in practical product of this reaction is 4′-methoxy[1,1′-biphenyl]-3-car- and scientific terms. Cross-coupling reactions catalyzed by boxylic acid (190) (Scheme 66). palladium complexes are widely used in modern organic synthesis as a reliable method of forming carbon–carbon OMe CO2H CO2H 0.1 mol% 'Pd' bonds in order to produce polyfunctional biaryls, arylated + olefins, acetylenes, and their heterocyclic analogs. Com- K2CO3, H2O Br 100 °C pounds of this type are key structural elements of a number B(OH)2 OMe of modern drugs,142 and are used to develop special purpose 188 189 190 polymeric materials.143 The Nobel Prize in Chemistry for Scheme 66 Model reaction - synthesis of 4′-methoxy[1,1′-biphenyl]-3- 2010 was awarded for studies of cross-combination reac- carboxylic acid tions, which attests to their high scientific and practical sig- nificance.144 As in the case of the palladium complex of acid 74, the The key parameter determining the efficiency of a cata- complexes of hydrazide 187a and phenylhydrazide 187b lyst in cross-coupling reactions is the nature of the ligand exhibit high catalytic activity in the Suzuki reaction, albeit on the palladium complex. Traditionally used phosphine li- slightly lower than that of the 4,5-dichloroisothiazole-3- gands are not suitable for large-scale use due to their toxici- carboxylic acid complex with palladium (Table 1). At the ty, their ease of oxidation, and their high cost, and there- same time, the catalytic activity of the hydrazide complex fore, the tendency over the last ten years to use heterocyclic was higher than that of the phenylhydrazide complex. carbenes, oxazolines, Schiff bases, and other nitrogen-containing compounds instead of phosphorus-containing li- Table 1 Characteristics of the Cross-Couplings of 3-Bromobenzoic gands is quite understandable.145 At the same time, from Acid with 4-Methoxyphenylboronic Acid Catalyzed by Complexes of Pal- the point of view of ecology and large-scale practical appli- ladium Chloride with 4,5-Dichloroisothiazole-3-carboxylic Acid (74)a cations of cross-coupling reactions, it would be optimal to use water as a reaction medium (‘green chemistry’).145–148 Pd complexb Time (min) Yield of 190 (%)c

One of the most important practical examples of cross-cou- b (74)2·Pd 15 100 pling reactions is the Suzuki reaction, which involves the c 187a·PdCl2 30 100 coupling of aryl and vinylboronic acids with aryl or vinyl 187b·PdCl d 60 96 halides, catalyzed by palladium complexes. The possibility 2 a Adapted from ref. 149. of extensive adjustment of the functional environment of b Complex (74)2·Pd: double salt; 187a·PdCl2: hydrazide; 187a·PdCl2: the chlorinated isothiazole, as well as the initial data on the phenylhydrazide. successful use of the 4,5-dichloroisothiazole-3-carboxylic c Determined from 1Н NMR data. acid complex with palladium chloride for the Suzuki reaction in aqueous medium, indicates a high potential for fur- Detailed studies on the influence of the functional envi- ther research into the design and synthesis of isothiazole li- ronment of the isothiazole heterocycle on the catalytic ac- gands for palladium complexes. tivity of the corresponding palladium complexes required During the first experiments, two of the most accessible the creation of new ligands. For this purpose, several new and simple derivatives of 4,5-dichloroisothiazole-3-carbox- derivatives were synthesized based on 4,5-dichloroisothi- ylic acid, i.e., its hydrazide 187a and phenylhydrazide 187b, azole-3-carboxylic acid, which contained different substit- were synthesized (Scheme 65).149 uents at position 3 of the heterocycle as well as additional

Palladium complexes of composition 187a·PdCl2 and coordination centers of various nature.

187b·PdCl2 were obtained by reacting compounds 187a and For this purpose, heterocyclic molecules containing

187b with Na2PdCl4 in methanol. Their catalytic activity 1,2,4-triazole or tetrazole rings together with an isothiazole was studied during the Suzuki reaction between 4-me- fragment have been synthesized.150 To construct a triazole thoxyphenylboronic acid (188) (which is prone to pro- heterocycle and to obtain (isothiazole)triazoles, an

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Syn thesis A. V. Kletskov et al. Review approach including initial synthesis of amidrazone 191 via The derivative 193 and its precursor amidrazone 191 the reaction of nitrile 89 with hydrazine hydrate was cho- were used for the synthesis of azole complexes. For a quali- sen (Scheme 67). tative assessment of the mutual influence of 1,2-azole and triazole fragments in mixed ligands, palladium complexes Me Ac with 1,2,4-triazole were also obtained. For the synthesized H N H 2 H N Cl CN AcCl 2 NH N Cl NNH2 N complexes, extremely low solubility was noted in organic N2H4·H2O Et3N Cl N AcOH Cl N N MeOH Et O solvents and in water, possibly due to their polymer struc- Cl S N 2 Cl S N Cl S N ture, and therefore they were characterized by IR spectros- Cl S 89 191 (80%) 192 (90%) 193 (85%) copy and elemental analysis. The model reactions present- Scheme 67 An example of the proposed approach towards (isothia- ed in Scheme 66 were carried out in 50% aqueous methanol zol-3-yl)triazoles (at 20 °C and 75 °C) or in water (at 100 °C) in the presence of 0.1 mol% of palladium complexes and potassium carbon- In order to obtain the target amidrazone, it was found ate as the base. All reactions were carried out in air in the that the reaction should be carried out with a minimal absence of an inert atmosphere. The results of testing the amount of methanol or without solvent at all, because oth- catalytic activity of the complexes are presented in Table 2. erwise the hydrazine hydrate does not react with the nitrile The resulting complexes, except for (191)2·PdCl2,

89. Amidrazone 191 was further treated with acetyl chlo- (194b)2·PdCl2 and (1,2,4-triazole)2·PdCl2, exhibited high cat- ride in the presence of triethylamine, and the resulting acyl alytic activity at elevated temperatures (i.e., 75 °C or derivative 192 was subjected to cyclization to give the tar- 100 °C). The palladium complexes with the isothiazole li- get 1,2,4-triazolylisothiazole 193 by heating in glacial acetic gands 191 and 193 were inert at room temperature, while acid followed by neutralization of the reaction mixture the (191)2·PdCl2 complex remained inactive even when with KOH solution (Scheme 67). The yield of 1,2,4-tri- heated, as did the (1,2,4-triazole)2·PdCl2 complex. The azolyl(isothiazole) 193 was 85%. (194b)2·PdCl2 complex exhibited only a slight catalytic ac- The nitrile group of carbonitriles 89 and 92b was used tivity at 100 °C. for the formation of tetrazole heterocycles (Scheme 68). The Later, the corresponding 3,5-isoxazolyl(isothiazolyl)- synthesis of tetrazolyl isothiazoles 194a,b was carried out substituted 1,2,4-oxadiazoles 195a–c were synthesized by by the reaction of sodium azide and ammonium chloride successive transformations of 5-(4-methylphenyl)isoxaz- with carbonitriles 89 and 92b in methanol, with good ole-3-carboxylic acid amidoxime 95 and 4,5-dichloroisothi- yields being obtained. azole-3-carboxylic acid amidoxime 196 (Scheme 69).151 Additionally, the 2,5-(5-aryl)isoxazolyl(isothiazolyl)- N N N substituted 1,3,4-oxadiazoles 197a–c were obtained by se- Cl CN NaN3 NH4Cl, 60 °C Cl H N lective recyclization of (4,5-dichloroisothiazol-3-yl)tetra- N MeOH, H2O R S N zole 194a (Scheme 70). R S Dichloromethane was the only solvent suitable for the 89, 194a: R = Cl (91%) 92b 194b: R = SPh (93%) preparation of complexes with representatives of the syn- Scheme 68 Synthesis of (isothiazol-3-yl)tetrazoles thesized ligands 195 and 197; the palladium benzonitrile complex (PhCN)2PdCl2 was used as the source of palladium. The complexes were characterized by their elemental

Ar COCl O H2N Cl N N N O Cl NOH Ar O O HCO2H Cl Ar Et N, THF H N O reflux, 3 h N N 3 2 S N Cl S 20 °C, 12 h Cl N N O 95 195a: Ar = 4-MeC H (58%) N 6 4 Cl S 195b: Ar = Ph (63%) Ar = 4-MeC6H4 (77%) Ar = Ph (98%) Cl Cl Cl Cl COCl Cl H2N S N O S NOH Cl N N S O HCO2H N N H2N O Ar N Et3N, THF reflux, 3 h O 20 °C, 12 h N Ar N Ar = 4-MeC H O 196 6 4 N 195c (86%) (94%) Ar O Scheme 69 Synthesis of 3,5-(5-aryl)isoxazol-3-yl(isothiazol-3-yl)-substituted 1,2,4-oxadiazoles

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R2 R1 R1 COCl N O X N N N Cl R1 R2 N N N Cl H N X N Cl 2 N N O R PhMe, reflux, 8 h – N2 N Cl N S N N X Cl S 194a 1 2 Cl N 197a: R = R = Cl; X = S (70%) S 1 2 197b: R = H; R = 4-MeC6H4; X = O (74%) 197c: R1 = H; R2 = Ph; X = O (82%) Scheme 70 Synthesis 2,5-(5-aryl)isoxazol-3-yl(isothiazol-3-yl)-substituted 1,3,4-oxadiazoles

Table 2 Characteristics of the Cross-Couplings of 3-Bromobenzoic Table 3 Yields of the Suzuki Reaction Product 4′-Methoxybiphenyl-3- Acid with 4-Methoxyphenylboronic Acid Catalyzed by Complexes of Pal- carboxylic Acid (190) Depending on the Pd Complex and Reaction Con- ladium Chloride with Ligands 191, 193 and 194ba ditionsa

Pd complex Temp (°C) Time (min) Yield of 190 (%)b Experiment Pd complex Temp (°C) Time (min) Yield of 190 (%)b

191·PdCl 20 20 traces 2 1 195c·2PdCl2 20 15 30 75 5 97 2 195c·2PdCl2 75 5 84 (191) ·PdCl 20 20 traces 2 2 3 195c·2PdCl2 100 1 100 100 30 traces 4 197a·PdCl2 20 15 0 193·PdCl 20 20 traces 2 5 197a·PdCl2 75 15 35 75 5 100 6 197a·PdCl2 100 50 93 (193) ·PdCl 20 20 traces 2 2 7 197b·2PdCl2 20 20 29 75 5 98 8 197b·2PdCl2 75 5 79 (194b) ·PdCl 20 120 0 2 2 9 197b·2PdCl2 100 5 100 100 5 5 10 (PhCN)2PdCl2 20 15 79 4 h 90 1,2,4-triazole·PdCl2 20 20 10 11 (PhCN) PdCl 75 15 96 75 5 100 2 2 a Adapted from ref. 151 with permission from Springer Nature. (1,2,4-triazole) ·PdCl 20 240 0 2 2 b Determined from 1Н NMR data. 100 240 0 a Adapted from ref. 150 with permission from Springer Nature. b Determined from 1Н NMR data. 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 analyses and IR spectroscopic data. In a model Suzuki reaction azomethines 198a,b (Scheme 72). In the case of the 4-ami- between 4-methoxyphenylboronic acid (188) and 3-bro- nobenzoic acid ethyl ester, this technique was not useful mobenzoic acid (189) (Scheme 71), it was shown that palla- due to only trace amounts of the target azomethine being dium complexes with these ligands exhibited high catalytic formed. When carrying out the reaction in boiling benzene activity in aqueous and aqueous–alcoholic media (Table 3). in the presence of catalytic amounts of glacial acetic acid, incomplete conversion of the starting aldehyde 106 into OMe CO2H azomethine 198c (40%) was observed, therefore the process CO2H 0.2 mol% ‘Pd’ K2CO3 (2.5 equiv) was carried out with higher-boiling toluene and an in- + MeOH–H2O 1:1 creased amount of acetic acid was used. Br 20 °C or 75 °C B(OH)2 or OMe Azomethines 198a–c were further reduced to give 188 189 H O, 100 °C 190 (1 equiv) (1.2 equiv) 2 amines 199a–c by the action of sodium borohydride and acetic acid in benzene, in 94–95% yields (Scheme 72). Re- Scheme 71 The model reaction for (isothiazol-3-yl)oxadiazoles palladium complexes catalytic activity testing duction 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. As another promising group of ligands for metal com- Amine 199c was further hydrolyzed into isothiazole amino plexes, N-aryl(isothiazol-3-yl)methyleneimines (aromatic acid 200 (Scheme 73). azomethines) and amines were synthesized.152,153 Conden-

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Syn thesis A. V. Kletskov et al. Review

Ar Ar based on their elemental analyses as well as IR spectroscop- Cl O NaBH4 ArNH2 Cl N AcOH Cl NH ic data, in which the characteristic vibration bands of the N AcOH, MeOH PhH Cl N N C=N and C=C bonds of the isothiazole heterocycle and the S Cl Cl S S corresponding exocyclic fragments were apparent. Accord- 106 198a (85%) 199a (95%) 198b (85%) 199b (95%) ing to their elemental analyses, they form complexes with

ArNH2 PhMe, AcOH palladium chloride with the composition LPdCl2. The com- Ar Ar = ; ; plexes are insoluble in organic solvents and in water, which Cl N NaBH Cl NH 4 198a, 199a 198b, 199b made it impossible to record their NMR spectra or to grow Ar AcOH, PhH N N CO Et single crystals for X-ray crystal structure analysis. The as- Cl S Cl S 2 198c (60%) 199c (94%) 198c, 199c sumption of their structure was made by analogy with the previously obtained palladium complexes with oxime li- Scheme 72 Synthesis of N-aryl(isothiazol-3-yl)methyleneimines (aro- 26 matic azomethines) and amines gands of the isoxazole series, 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 palladi- O um. For the complex of the isothiazole amino acid 200 with CO2H Cl Cl OEt H+, 85 °C palladium chloride, calculations of the geometry and IR H2O Cl N spectrum were made at the B3LYP/6-31+G*/ Cl N H H S N S N LANL2TZ(f)ECP(Pd) level of theory. As a result, it was pro- 199c 200 (99%) posed that the isothiazole ligand 200 in the molecules of Scheme 73 Deprotection of carboxylic group in compound 199c the complex 200·PdCl2 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 five- Azomethine 198b, amine 199b, and isothiazole-con- membered metallocycle (Figure 5). taining amino acid 200 (from the synthesized aromatic Evaluation of the catalytic activity of the obtained com- azomethines and amines) were used as ligands in order to plexes on the model reaction presented in Scheme 66 was obtain palladium(II) complexes by reaction with sodium performed under conditions similar to those used in previ- 149,150 tetrachloropalladate. Complexes of the composition LPdCl2 ous tests. The results of the testing of the catalytic ac- were formed by the interaction of equimolar amounts of tivity of the complexes are presented in Table 4. sodium tetrachloropalladate and the ligands in methanol at 20 °C. Since acid 200 was poorly soluble in both methanol Table 4 Characteristics of the Cross-Couplings of 3-Bromobenzoic and acetonitrile, which were previously used to produce Acid with 4-Methoxyphenylboronic Acid Catalyzed by Palladium Chlo- 1,2-azole palladium complexes, the complex was synthe- ride Complexes with Ligands 198b, 199b and 200a sized in a mixture of methanol and DMF, in which derivative 200 is quite soluble. The obtained palladium complexes Pd complex Temp (°C) Time (min) Yield of 190 (%)b 198b·PdCl , 199b·PdCl , and 200·PdCl were identified 2 2 2 198b·PdCl2 20 30 67 75 20 96

199b·PdCl2 20 30 42 100 30 100

200·PdCl2 (in situ potassium 35 5 100 salt) 100 3 100

Na2PdCl4 20 5 87 20 240 92

Na2PdCl4 75 5 99 a Adapted from refs. 152 and 153 with permission from Springer Nature. b Determined from 1Н NMR data.

The reactions were complete in 3–30 minutes with the formation of 4′-methoxy[1,1′-biphenyl]-3-carboxylic acid Figure 5 Structure of the complex of isothiazole-containing aromatic (190), the target product of the cross-coupling, with yields amino acid 200 with palladium chloride, obtained using quantum- of 96–100%. In each case, the formation of palladium black chemical modeling at the B3LYP/6-31+G*/LANL2TZ(f)ECP(Pd) level of did not occur until the end of the reaction. Analysis of the 153 theory (reproduced with permission from Springer Nature) reaction mixtures by TLC at the time of separation of the

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Syn thesis A. V. Kletskov et al. Review palladium black consistently showed the absence of aryl 6 Conclusion halide. The solution itself remained almost colorless, which indirectly indicates a low content of colloidal (nanoscale) The presented and summarized data, published mainly palladium in the reaction mixture and products. over the past 18 years, demonstrates the intensive develop- According to the obtained data, the palladium complex- ment of isothiazole chemistry and highlights the rich po- es with one ligand (LPdCl2) were significantly more active tential of isothiazole derivatives both for organic synthesis than those with two ligands (L2PdCl2). The complex with and practical use. the isothiazole derivative 200 was the most active among New data on the design of isothiazole heterocycles and all the complexes tested, and its activity was especially no- the synthesis of isothiazole derivatives has been considered ticeable at 20–35 °C. It should also be noted that the forma- from the standpoint of retrosynthetic analysis, which al- tion of a small amount of the arylboronic acid homocou- lows four rational approaches for the formation of the iso- pling product, 4,4′-dimethoxy-1,1′-biphenyl (with yields of thiazole rings to be distinguished: intramolecular cycliza- 1–3%), was observed in the reactions in all cases. Since the tion, (4+1)-heterocyclization, (3+2)-heterocyclization and reactions were carried out in the absence of an inert atmo- synthesis based on other heterocyclic compounds. Such sphere, it is possible that the by-product was formed be- classification enables a consistent and logical understand- cause of oxidation of the starting arylboronic acid by aerial ing of the available approaches to obtaining substituted iso- oxygen during the catalysis with palladium, but the contri- thiazoles, and in some cases, to predict the most rational bution of this process is considered negligible. Complex 200 synthetic methods thereof. was used for the preparation of a heterogeneous silicon- The largest part of the published information is covered oxide-supported catalyst, and its catalytic properties were in the section dedicated to the target functionalization of almost as good as the complex itself and it was able to substituted isothiazoles. This data demonstrates the rich withstand at least 10 catalytic cycles.154 possibilities of the developed strategies for successive The observed temperature dependence of the catalytic transformations of isothiazole derivatives. Chlorinated iso- activity of the described isothiazole complexes can be used thiazoles seem particularly promising as starting com- to control the selectivity of the cross-coupling reactions in pounds in this regard. molecules with several reaction centers. Isothiazole palladi- The logical continuation of such functionalizations is a um complexes are suitable for chemical and chemical-phar- separate section devoted to biologically active isothiazoles. maceutical processes in cases where the synthesis of the In recent years, a large number of molecules containing the target substances is carried out using the Suzuki reaction isothiazole fragment have been proposed as bioactive sub- and high purity requirements are imposed on the final stances capable of selectively conjugating with key enzyme product. sites. There are various strategies for the formation of such We are confident that the data on isothiazole–metal molecules, which have been illustrated in detail. The most complexes summarized above, as well as the information common strategy is sequential multistep synthesis based on the catalytic and biological activity of their representa- on isothiazole cores with reactive substituents. This meth- tives, can stimulate further research in this very promising od is used for the synthesis of a number of isothiazoles pos- area. At the same time, we believe that while the synthesis sessing significant antimitogenic activity. Sufficiently high of new metal complexes of the isothiazole series and the interest is represented by published data on isothiazoles study of their properties definitely deserves the attention that exhibit synergistic effects in compositions with known of modern researchers, so also does the study of the practi- anticancer drugs and pesticides. It is hoped that the re- cal utilization of the isothiazole complexes that were previ- search in this field will continue to develop rapidly and will ously described in the literature. unite the efforts of both chemists and specialists in the The above information on isothiazole complexes, as far fields of biochemistry and medicine. as we know, is comprehensive. In an earlier review on the A separate section is devoted to isothiazoles in the syn- coordination chemistry of thiadiazoles, thiazoles and iso- thesis of transition-metal complexes and in metal-complex thiazoles, isothiazole–metal complexes were given little catalysis. There is a great future for research in this field of more than one page, with only five papers on this topic be- isothiazole chemistry, especially in the development of ing considered.155 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

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