Russian Chemical Reviews 71 (8) 673 ± 694 (2002) Isothiazoles (1,2-thiazoles): synthesis, properties and applications R V Kaberdin, V I Potkin Contents I. Introduction II. Synthesis of isothiazoles III. Chemical transformations of isothiazoles IV. Areas of application of isothiazoles V. Conclusion Abstract. of chemistry the in achievements recent most The The most recent achievements in the chemistry of isothiazoles are generalised and systematised. The main applica- isothiazoles are generalised and systematised. The main applica- tions of isothiazole derivatives are surveyed. The bibliography tions of isothiazole derivatives are surveyed. The bibliography includes references 293 includes 293 references. I. Introduction Isothiazoles constitute a relatively novel class of heterocyclic compounds.Their ancestor, 1,2-thiazole, was first obtained in 1956.1 Other 1,2-azoles had been rather well studied by that time, both theoretically and with respect to their practical applications. Further rapid progress in the chemistry of isothiazole and intense studies into the synthesis and chemical conversions of its deriva- tives carried out in the 1960 ± 1990's were caused primarily by the extraordinarily broad range of useful properties manifested by various representatives of this class of compounds. Isothiazole- containing penicillins and cephalosporins competed successfully with ampicillin in their activities against gram-positive and gram- negative bacteria.2, 3 In the last decade of the 20th century, some isothiazole derivatives were found to be efficient in the treatment of Alzheimer's disease,4 as antiinflammatory, antithrombotic and anticonvulsive drugs 5, 6 and serine protease inhibitors;7, 8 physio- logically active compounds interacting with glutamate receptors were synthesised.9 Auxin transport inhibitors based on isothia- zoles 10 ± 14 are added to herbicides to enhance their activity.Isothiazole derivatives manifest synergistic effects when added to other biocidal preparations.15 ± 19 Compositions containing iso- thiazole derivatives are used as protectors for polymers, dyes, detergents 20 and leather goods,21 for decontamination of pig- ments, latexes, foodstuffs 22 and waste,23 as antifouling agents,24, 25 etc.Recently, isothiazoles have been patented for use in colour photography for stabilisation of photomaterials 26, 27 and as an inkbase for printers.28, 29 Industrial production of some isothiazolones, which represent broad-spectrum biocides and are safe for human beings, animals and environment, has begun.30 R V Kaberdin, V I Potkin Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, ul. Surganova 13, 220072 Minsk, Belarus. Fax (37-517) 284 16 79. Tel. (37-517) 284 16 00. E-mail: ifoch@ifoch.bas-net.by (R V Kaberdin) Tel. (37-517) 284 09 72. E-mail: potkin@ifoch.bas-net.by (V I Potkin) Received 3 June 2002 Uspekhi Khimii 71 (8) 764 ± 787 (2002); translated by R L Birnova #2002 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2002v071n08ABEH000738 673 673 684 690 691 The first data on the chemistry of isothiazoles were reviewed by Wooldridge et al.31, 32 Further progress in the synthesis and conversions of isothiazoles is documented in the reviews 33 ± 39 some of which are inaccessible for Russian readers as well as in the monographs 40 ± 45 where isothiazoles are considered only in con- junction with other heterocyclic compounds.The fundamental monograph by Houben-Weyl,46 which contains more than 500 references including some published in 1992, represents the most systematic and full generalisation of the experimental data on the chemistry of 1,2-thiazoles. The first review devoted to the physical and chemical properties of 1,2-azoles was published in Russian in 1979.47 In addition, isothiazoles and their benzoannelated ana- logues are discussed in `Comprehensive Organic Chemistry'.48 The necessity for systematisation and generalisation of the newest data on isothiazoles stems from the appearance, in the past decade, of a great number of publications devoted to the synthesis, conversions and applications of this class of compounds.The material described here covers original papers and patent data published over the period 1993 ± 2001 inclusive. In some cases, earlier sources concerned with the methods for isothiazole syn- thesis are cited for the sake of completeness. II. Synthesis of isothiazoles Isothiazole (1) was first prepared by the oxidation of 5-amino-1,2- benzoisothiazole (2) with an alkaline solution of potassium permanganate with subsequent decarboxylation of isothiazole- 4,5-dicarboxylic acid (3).1, 49 HO2C H2N N N N HO2C S S1 S3 2 This synthetic procedure has a purely historical significance. Later, isothiazoles were synthesised from simpler and more accessible compounds.1. Synthesis of isothiazoles based on cyclisation reactions The main methods for the construction of the isothiazole ring are based on cyclisation of compounds containing N7C7C7C7S fragments and heterocyclisation of compounds containing nitro- gen, sulfur and carbon atoms.674 a. Synthesis of isothiazoles from compounds containing the N7C7C7C7S group The construction of the isothiazole ring from compounds con- taining a preformed N7C7C7C7S fragment is the most attractive approach.Thus various 5-aminoisothiazole derivatives 4 can be prepared by the oxidation of 2-aminoalk-1-enethiocar- boxyamides 5.50 R S H2N I2, K2CO3, Et2O C CHC NH2 N H2N 5 R S4 R=Et, Pri, Bun, Bui, But, cyclo-C6H11. NR2 S Oxidation of 3-amino-3-(dialkylamino)thioacrylic acid amid- es 7 gives the 3,5-diaminoisothiazole derivatives 6.51 H2N oxidiser C CH C NH2 N H2N 7 R2N S6 R=Alk. A procedure for the synthesis of alkyl 3-methyl-5-ethoxycar- bonylaminoisothiazole-4-carboxylates (8) by the oxidation of substituted thioamides 9 with selenium dioxide has been devel- oped recently.52 Me RO2C S H2N SeO2 C C C NHCO2Et EtOH, 40 8C N EtO2CHN Me CO2R S8 9 R=Me, Et.b. Synthesis of isothiazoles from sulfur and compounds containing the C7C7C7N fragment The construction of the isothiazole ring from sulfur and com- pounds containing the C7C7C7N fragment is relatively little studied. This approach makes use mainly of nitriles.46 Thus the electrolysis of 3-aryl-2-phenylsulfonylacrylonitriles (10) in acetonitrile or DMF using a chemically active sulfur ± graphite electrode affords bis(5-arylisothiazol-3-yl) di- or tri- sulfides (11).53 Sn S N ArCH CC N N Ar Ar SO2Ph S S 11 10 Ar=Ph, 4-MeC6H4, 4-PhC6H4; n=2, 3. In the case of 2-phenyl-3-phenylsulfonylacrylonitrile (12), di(isothiazolyl) disulfide 13 containing the (Z)-2-cyano-2-phenyl- vinylthio group in position 3 of one of the isothiazole rings was obtained.53 Ph HC C C N Ph S S S S N PhSO2CH CC N N Ph S S Ph 13 12 It is believed that electrochemical synthesis of sulfur-contain- ing compounds consists in the elimination of the phenylsulfonyl group with concomitant addition of a polysulfide anion produced upon electroreduction of elemental sulfur.R V Kaberdin, V I Potkin According to the patent data,54 substituted a-amino ketones react with thionyl chloride to give the corresponding 4-hydroxy- isothiazoles. Thus the reaction of amino ketone 14 with SOCl2 in DMF yields isothiazole 15. When thionyl chloride was used in excess, the reaction products contained both isothiazole 15 and di(isothiazolyl) sulfide 16. SOCl2 PhCH2COCHPh DMF 14 NH2 Ph OH HO Ph Ph HO + N N N Ph S S S S 15 (62%) 16 The authors of the present review together with Yu A Olde- kop have demonstrated 55 ± 57 that heating of 2-nitropentachlo- robuta-1,3-diene (17) with sulfur resulted in its heterocyclisation and the formation of 4,5-dichloro-3-trichloromethylisothiazole (18).Cl CCl3 S, 190 ± 200 8C Cl2C CCl C CCl2 7SO2 N Cl NO2 17 S 18 This reaction offers a new approach to the construction of the isothiazole ring. It is known that the reaction of halobutenes and -butadienes with sulfur is used for the synthesis of the correspond- ing halogenothiophenes.58 In the case of nitrodiene 17, the reaction follows a different route: the heterocyclisation involves the nitro group and is accompanied by the evolution of sulfur dioxide. The yield of isothiazole 18 reaches 52%.Tetrachloro- thiophene (yield 4%) is the side product in this reaction. Appa- rently, the reaction has a radical character, since sulfur molecules exist in the form of reactive biradicals Sn at high temperature.59 c. Synthesis of isothiazoles using cycloaddition and condensation reactions The methods for the synthesis of isothiazoles using cycloaddition and condensation reactions of compounds containing a set of essential fragments are the most well-studied and attract, as before, the attention of investigators. Thus the 1,3-dipolar cycloaddition of nitrile sulfide 19 to dimethyl acetylenedicarboxylate (20) yields the isothiazole deriv- ative 21 the structure of which has been confirmed by X-ray diffraction analysis.60 R MeO2C + 7 N R C N S+MeO2C C C CO2Me 19 20 MeO2C 21 S R=The reactions of 1-cyano-3-(2-oxo-1,3,4-oxathiazol-5-yl)ada- mantane (22) and 1,4-bis(2-oxo-1,3,4-oxathiazol-5-yl)adaman- tane (23) prepared from the corresponding adamantanecarbox- amides and chlorosulfenylcarbonyl chloride with the alkyne 20 result in the decarboxylation of the oxathiazolone fragment.The reactions of the nitrile sulfides formed with the alkyne 20 proceed as 1,3-dipolar cycloadditions and yield 1-cyano-3-(4,5-dimeth- oxycarbonylisothiazol-3-yl)adamantane (24) and 1,3-bis(4,5- dimethoxycarbonylisothiazol-3-yl)adamantane (25), respec- tively.61675 Isothiazoles (1,2-thiazoles): synthesis, properties and applications O R2 CN CN R2 H2N O HN S HN N ClCOSCl 20, D N N HN O H2NC(O) S CONH2 N O S 29b 31 30 O R2 N S 22 CN HO BnO O O CO2Me R1= (29a), R2= (29b, 30, 31).HO OH BnO OBn CO2Me N S 24 O S CONH2 O N ClCOSCl 20, D The use of 1,3,5-trichloro-1,3,5,2,4,6-trithiatriazine (32) seems to be very promising for the synthesis of isothiazoles. It was found that ordinary allylic compounds of the type 33 react with the reagent 32 as two-carbon units to give 1,2,5- thiadiazoles 34 and as three-carbon units to give isothiazoles 35. The ratio of compounds 34 and 35 depends on the reaction conditions and the nature of the substituents.64 CONH2 O Cl O S N S N N 23 S S CO2Me Cl Cl S N32 N CO2Me R1 CH CHCH2R2 33 R2 R1 CH2R2 CO2Me + N N N CO2Me R1 N S 25 S 35 S 34 The reaction of nitrile sulfides of the thiophene series with dimethyl fumarate (26) gives substituted 4,5-dihydroisothiazoles 27.62 R O D RCONH2+ClCOSCl 70 ± 110 8C PhMe 7CO2 N O S Thus 1,3-diphenylpropene (33, R1=R2=Ph) reacts with two equivalents of compound 32 in boiling CCl4 to give 3,5- diphenylisothiazole 35 in 53% yield. The introduction of a substituent at the central carbon atom of the allylic system suppresses the formation of thiadiazoles.4-Methyl-3,5-diphenyl- isothiazole was obtained from 2-methyl-1,3-diphenylpropene without any admixtures of the corresponding thiadiazole. H MeO2C Ph Me C C 32 R Ph CH CCH2Ph H CO2Me + 26 7 N R C N S Ph Me S N MeO2C H H MeO2C S 27 The presence of terminal electron-withdrawing groups in the allylic derivatives 33 increases their reactivities with respect to the reagent 32.64 , , R= Me SMe Me SO2Me S S S In the case of non-symmetrical allylic compounds, the reac- tion proceeds regiospecifically and affords an isomer with the electron-withdrawing group adjacent to the sulfur atom of the ring.Thus the reaction of the trimer 32 with ethyl 3,3-dibenzyl- acrylate affords isothiazole 36 in 66% yield.64 Ph Bn CH2Ph 32 EtO2CHC C N EtO2C Bn The cycloaddition of 3,4,6-tri-O-benzyl-2,5-anhydro-D-allo- nonitrile N-sulfide (28) to dimethyl acetylenedicarboxylate (20) or dimethyl fumarate (26) followed by the oxidation of the reaction products with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) results in O-benzyl-3-(b-D-ribofuranosyl)isothiazoledi- carboxylate 29a, which was used for the preparation of the C-nucleoside 29b and isothiazolo[4,5-d ]pyrimidine analogues of the natural C-nucleosides pyrazofurin (30) and formycin (31).63 S 36 S N C BnO O R1 MeO2C 20 or 26+DDQ Trithiatriazine trichloride 32 can be used for the preparation of isothiazole derivatives from other heterocyclic compounds.It was shown 65 ± 67 that treatment of di- and trisubstituted N MeO2C OBn S 29a BnO28 furans 37a ± c with trithiatriazine trichloride 32 in boiling CCl4 results in their one-step conversion into 5-benzoylisothiazoles 38a ± c in high yields.676 Ph R R 32 Ph N Ph Ph O S 38a ± c O 37a ± c R = H (a), Ph (b), Br (c).2,5-Disubstituted furans 39a ± c give similar products 40a ± c (yields 50% ± 60%) with compound 32 upon boiling in CCl4 or toluene.65 R 32 N RC R R CCl4, D S O 40a ± c O 39a ± c R=4-MeC6H4 (a), 4-MeOC6H4 (b), But (c). It is assumed that heating of 1,3,5-trichloro-1,3,5,2,4,6-tri- thiatriazine (32) results in its fragmentation and the formation of the reactive monomer A which attacks the furan molecule to give the intermediate B. Recyclisation of the latter affords isothia- zoles.65 Cl S N N + 7 N S Cl 3 N S Cl S S A N Cl Cl 32 N N S Cl H S R R N 7HCl R R R R O O S 40 OB It has been shown 68 that fully substituted furans do not react with the reagent 32, since the elimination of HCl requires the presence of a hydrogen atom in the b-position of the starting furan.Yet another route to the synthesis of 5-acylisothiazoles 41 is based on the reaction of 2,5-disubstituted furans with ethyl carbamate, SOCl2 and pyridine.68 R2 NH2CO2Et, SOCl2 R1 N Py, PhH, D R2 R1 O O S 41 R1=R2=Ph, 4-MeC6H4, But; R1=4-MeOC6H4, R2=4-NO2C6H4. In contrast with 2,5-diphenylfuran (37a), the reaction of 2,5- diphenylthiophene (42) with the reagent 32 gives 5-benzoyl-3- phenylisothiazole (38a) in low yield. Presumably, the latter is formed upon oxidation of the intermediate 5-thiobenzoyl deriva- tive 43.69 Ph Ph 32 Ph Ph Ph CCl4 Ph N N S S S 42 O S 38a 43 Reactions of N-substituted 2,5-diphenylpyrroles 44a ± e with compound 32 afford mixtures of thiazolyl-substituted imines 45a ± e and 3,4-dichloropyrrole derivatives 46a ± e.The ratio of the reaction products depends on the nature of the substituent R.69 R V Kaberdin, V I Potkin Ph Cl Cl 32 + Ph Ph Ph CCl4 N Ph Ph NR S NRNR 44a ± e 46a ± e 45a ± e R=Ph (a), 4-MeOC6H4 (b), 4-O2NC6H4 (c), MeOC(O) (d), ButOC(O)H (e). Compounds 45b,e are formed as two geometrical isomers. Imine 45b is easily hydrolysed to give ketone 38a. The imine 45d formed from N-methoxycarbonylpyrrole (44d) is completely hydrolysed even at room temperature to give ketone 38a. It is of note that the reaction of 1-methyl-2,5-diphenylpyrrole (47) with the reagent 32 follows a different route and results in the formation of bi(1,2,5-thiadiazol-3-yl) 48; 5-benzoyl-3-phenyliso- thiazole (38a) is formed in only trace amounts.69 Ph N 32 S N +38a Ph Ph CCl4 N S N NMe Ph 48 47 Condensation of 2-dialkylaminomethyldithiomalonates 49, the reaction products of dithiomalonates 50 with formamide acetals, with hydroxylamine-O-sulfonic acid results in isothiazoles 51.70 C(S)OR1 H2C +R22 NCH(OR3)2 C(S)OR1 S 50 C R1O C(S)OR1 NH2OSO3H R22 NCH2CH N R1O C(S)OR1 49 S 51 R1, R3=Me, Et; R2=Me, Ph.Schulze et al.71 have developed two procedures for the syn- thesis of isothiazoles 52a ± c containing fluoro-substituted aryl groups.The first of them is based on the reaction of b-thiocyana- tocinnamaldehydes 53a,b with ammonium thiocyanate (54). Iso- thiazoles 52a,b were obtained in good yields (*60%). In this case, ammonium thiocyanate (54) acts as a source of ammonium required for ring closure. It is noteworthy that ammonium thiocyanate (54) was employed previously for the preparation of 4- and 5-alkylisothiazoles.72 The second route is based on the use of enamino thiones 55a ± c as starting compounds; their reaction with hydroxylamine- O-sulfonic acid gives isothiazoles 52a ± c. In this case, the yields reach 98%.CHO NH4SCN (54) Ar SCN 53a ± c N NMe2 Ar S 52a ± c NH2OSO3H Py, MeOH Ar S 55a ± c Ar=4-CF3C6H4 (a), 3-CF3C6H4 (b), 3-FC6H4 (c).Approaches to the synthesis of isothiazolium salts 56 were developed based on cinnamaldehydes 53a,b,d,e and enamino thiones 55d ± g.71Isothiazoles (1,2-thiazoles): synthesis, properties and applications CHO H2NAr2 HClO4 SCN Ar1 53a,b,d,e + N Ar2 Ar1 ClO¡ NHAr2 4 H2O2, AcOH S 56 HClO4 Ar1 S 55d ± g Ar1=4-CF3C6H4 (53a, 55f), 3-CF3C6H4 (53b, 55g), 4-FC6H4 (53d, 55d), 4-MeOC6H4 (53e, 55e); Ar2=Ph, 4-MeOC6H4. 4-Thiocyanato-1-aza-1,3-dienes 57 prepared from b-thiocya- nato a,b-unsaturated aldehydes 58 and arenesulfonohydrazides 59 undergo cyclocondensation to yield N-arylsulfonylisothiazol- 2-ylimines 60 and the corresponding N-arylsulfonyl-2-aminoiso- thiazolium salts 61.73 CH R1 R1 HCl NNHSO2Ar MeOH CHO+H2NNHSO2Ar 59 SCN R2 R2 57 SCN 58a ± e R1 + N 7 R2 NSO2Ar S 60 HClO4 base R1 HClO4 + ClO¡4N R2 NHSO2Ar S 61 R1=R2=Me (a); R1=Ph, R2=Me (b); R17R2=(CH2)n, n = 3 (c), 4 (d), 5 (e); Ar=Ph, 4-MeC6H4, 4-BrC6H4, 2,4,6-Me3C6H2, 2,4,6-Pri3C6H2.Thus, depending on the nature of the substituents R1, R2 and Ar, the reactions of unsaturated thiocyanato aldehydes with arenesulfono hydrazides afford different products. Isothiazoles are formed directly from compounds 58a,b, whereas alicyclic thiocyanato aldehydes 58c ± e yield stable hydrazones 57. Treat- ment of the latter with perchloric acid yields isothiazolium salts 61c ± e. A convenient procedure for the synthesis of N-acylisothiazo- lidinium trifluoroacetates 62, which includes treatment of N-acyl- amino sulfoxides 63 with trifluroacetic anhydride, has been developed.74 (CF3CO)2O N PhS(CH2)3NHCOR COR MeCN, 0 8C +SCF3CO¡263 O Ph 62 R=But, Ph.2. Synthesis of isothiazoles from other heterocyclic compounds Methods of synthesis of substituted isothiazoles from other heterocyclic compounds find wide application despite the fact that they belong to the most ancient ones. Thus 3,5-disubstituted isothiazoles 64a,b were prepared from isoxazoles 65a,b by the reaction with phosphorus pentasulfide in pyridine.75 677 Me HO Me HO P2S5 Py N N 4-RC6H4 4-RC6H4 S 64a,b O 65a,b R = H (a), MeO (b). The reaction of 2-imino-3,4-dihydro-2H-pyrrole 66 with sul- fur on heating is accompanied by dehydrogenation and incorpo- ration of the sulfur atom into the pyrrole ring resulting in the previously unknown thiazolylisothiazoles 67.76 Ph Ph Ph Ph CHPh S S N D Ph Ph N Ph N S N 67 66 The thermal fragmentation of 1,4,2-dithiazines in the presence of dienophiles aimed at the synthesis of 1,4-dithyines has been studied.74 It was found that 1,4,2-dithiazine derivatives 68 react with dimethyl acetylenedicarboxylate (20) on heating in o-dichlo- robenzene to give a mixture of dimethyl 4,5-dimethylthiophene- 2,3-dicarboxylate (69) and 3-(4-bromophenyl)-4,5-dimethyliso- thiazole (70).The latter is formed upon thermolysis of dithiazine 68 and is accompanied by a loss of the sulfur atom from position 4.77 Me S C6H4Br-4 MeO2C C C CO2Me 20 180 8C Me S N 68 Me Me C6H4Br-4 CO2Me + N Me Me CO2Me S 70 (34%) S 69 (20%) A new method for the synthesis of the isothiazole ring from 4-chloro-5-dicyanomethylidene-5H-1,2,3-dithiazole (71) pre- pared by the condensation of 4-chloro-1,2,3-dithiazole-5-thione with tetracyanoethylene oxide has been proposed recently.Treat- ment of the nitrile 71 with morpholine or benzyltriethylammo- nium chloride gives 3-morpholino- (72a) and 3-chloroisothiazole- 4,5-dicarbonitriles (72b), respectively.78 Cl S CN NC + N S CN NC O S O O HN N NC CN N Cl NC NC S 72a N S Cl NC BnEt3NCl +7 S 71 N NC S 72b A new simple procedure for the synthesis of isothiazoles from primary enamines and 4,5-dichloro-1,2,3-dithiazolium chloride (73) has been developed.Thus the reaction of methyl 3-amino- crotonate (74a) and 3-aminocrotononitrile (74b) with the salt 73 under mild conditions (20 8C, dichloroethane) afforded678 4-methoxycarbonyl-5-cyano-3-methylisothiazole (75a) and 4,5- dicyano-3-methylisothiazole (75b).79 Cl NH2 + N Me C CHR+ S Cl7 74a,b S 73 R=CO2Me (a), CN (b). Presumably, the conversion of enamine 74a into isothiazole 75a upon treatment with the salt 73 proceeds similarly to its conversion into isothiazole 76 under the action of thiophosgene used by Woodword et al. in the synthesis of colchicine back in 1965.80 NH2 CSCl2 Me C CH CO2Me 74a Me MeO2C N S 76 3. Synthesis of isothiazole derivatives by modification of compounds containing the isothiazole ring The syntheses of functionalised isothiazoles by exchange of substituents in the isothiazole ring or by transformation of the side chain of accessible derivatives are well documented.46 a.Substitution reactions Recently, Russian chemists have developed novel procedures for the synthesis of halogenated isothiazoles.81 ± 83 Thus bromo- and iodoisothiazoles 78 ± 83 have been synthesised from the readily available 3-hydroxyisothiazole (77).81 POBr3 OH H2SO4 NBS N Br S 77 PBr5 NBS, N-bromosuccinimide. Br I HIO4 I2 78 N S 80 Br Br2 oleum Br 79 Br HIO4 I2H2SO4 I R Me Cl N NC S 75a,b CO2MeCl Et3N Me C 72 HCl Cl H2N S Br N S 78 Br N S 79 Br I HIO4 I2 N I H2SO4 S 81 Br N S 82 Br N S 83 R V Kaberdin, V I Potkin The possibility of synthesis of alkenylhaloisothiazoles by palladium-catalysed cross-coupling of the halogen derivatives 80 and 83 with the terminal alkenes 84a ± d (the Heck reaction) has been studied.82 It was found that 3,4-dibromo-5-iodoisothiazole (83) does not react with alkenes under the reaction conditions.3-Bromo-4-iodoisothiazole 80 enters into the Heck reaction with the alkenes 84a ± c in the presence of the catalytic system Pd(OAc)2 ± NEt3 to give 4-alkenyl-3-bromoisothiazoles 85a ± c. 4,40-Bi(3-bromoisothiazole) (86) is the side product in this reac- tion; it is also formed in the absence of the alkene. Br I Pd(OAc)2 ± NEt3 +CH2 N MeCN, 100 8C CHR 84a ± c S 80 Br Br Br RHC CH + N N N S S 86 (9% ± 13%) S 85a ± c R=Ph (a, 60%), CO2Me (b, 29%), CN (c, 33%).3-Bromo-4-(1-oxopropan-2-yl)isothiazole (87) and biisothia- zolyl 86 were isolated from a complex mixture of reaction products of isothiazole 80 with allyl alcohol (84d). Me OHC Br Br HC I +86 (13%) CHCH2OH +CH2 N N 84d S 87 (6%) S 80 Under conditions of metal-complex catalysis, bromo- and iodoisothiazoles react with terminal alkynes.83 Thus tribromoiso- thiazole (82) reacts with phenylacetylene (88a), oct-1-yne (88b), propargyl alcohol (88c) and methoxymethylacetylene (88d) in the presence of (PPh3)2PdCl2 even at 20 8C to give the cross-coupling products (89a ± d).Br Br Br Br (PPh3)2PdCl2, CuI, NEt3 N N C RC Br +RC CH 88a ± d S 89a ± d S 82 R=Ph (a), n-C6H13 (b), CH2OH (c), CH2OMe (d). The highest yields (20% ± 56%) were obtained with 4 mol.% of (PPh3)2PdCl2 . 1,4-Diphenylbuta-1,3-diyne was isolated as a side product in the reaction of isothiazole 82 with phenylacetylene 88a.It should be noted that unsubstituted acetylene does not enter into the cross-coupling reaction with isothiazole 82 even at 80 8C; the reaction mixture contained only 3,4-dibromoisothiazole (79), the partial reduction product of the tribromide 82. Compound 79 did not react with phenylacetylene, i.e., only the bromine atoms in position 5 were active in the cross-coupling reaction. 5-Iodoiso- thiazoles were found to be the most reactive compounds.The reactions of 3,4-dibromo-5-iodoisothiazole (83) and 3-bromo-4,5- diiodoisothiazole (81) with terminal alkynes 88a,d occur in the presence of 2 mol.% of (PPh3)2PdCl2 and result in the corre- sponding 3,4-dibromo-5-alkynyl- (90) and 3-bromo-4-iodo-5- alkynylisothiazoles (91a,b).Isothiazoles (1,2-thiazoles): synthesis, properties and applications Br X Br X (PPh3)2PdCl2, CuI, NEt3, MeCN +RC CH N N C RC I 88a,d S 90, 91a,b S 81, 83 R X Compounds Br 90 91a 91b Ph I Ph I CH2 OMe The side reaction products of terminal alkynes with 3,4- dibromo-5-iodoisothiazole (83) and 3-bromo-4,5-diiodoisothia- zole (81), viz., the dibromide 79 and 3-bromo-4-iodoisothiazole (80), represent the reduction products of iodine in position 5.3-Bromo-4-iodoisothiazole (80) enter into cross-coupling reactions with phenylacetylene (88a) under conditions of metal- complex catalysis to give 3-bromo-4-(phenylethynyl)isothiazole (92).83 Br PhC C Br I +PhC CH N N (PPh3)2PdCl2, CuI, NEt3, MeCN 50 8C 88a S 92 (49%) S 80 3-Bromo-4-(3-methoxyprop-1-ynyl)-5-(phenylethynyl)isothi- azole (93), the first representative of isothiazoles with two alkynyl substituents, was synthesised by the reaction of 3-bromo-4-iodo- 5-(phenylethynyl)isothiazole (91a) with methoxymethylacetylene (88d) under similar conditions.83 Br C Br I MeOCH2C +MeOCH2C CH N N C PhC C PhC 88d S 91a S 93 (42%) 4,5-Dichloro-3-trichloromethylisothiazole (18) reacts smo- othly with various nucleophilic reagents resulting in the substitu- tion of the chlorine atom in position 5 of the isothiazole ring.Thus its reactions with sodium methoxide, ethoxide and isopropoxide afford the corresponding 5-alkoxy-4-chloro-3-trichloromethyli- sothiazoles (94a ± c) in 73%± 78% yields. The reaction of isothia- zole 18 with piperidine results in 4-chloro-5-piperidino-3- trichloromethylisothiazole (95).56 Cl CCl3 RONa N RO Cl CCl3 S 94a ± c R=Me (a), Et (b), Pri (c) N Cl Cl CCl3 S 18 HN N N S 95 (85%) The reaction of methyl 4,5-dichloroisothiazole-3-carboxylate (96) with sodium methoxide in methanol at 20 8C proceeds in a similar way and yields methyl 5-methoxy-4-chlorothiazole-3- carboxylate (97).84 At a higher temperature, the saponification of the ester 96 occurs.The reaction of sodium methoxide with 4,5-dichloroisothiazole-3-carboxylic acid piperidide (98) prepared by treatment of the ester 96 with piperidine yields compound 99, the substitution product of the methoxy group for the chlorine atom in position 5.84 Cl CO2Me N Cl S 96 Cl HN 96 Cl Cl MeO S 99 (32%) A vast variety of 4-aroyl- and 4-hetaroylisothiazoles were prepared from substituted 4-iodoisothiazoles.85 ± 88 This is exem- plified in the synthesis of 5-cyclopropyl-4-(2-methylsulfonyl-4- trifluoromethylbenzoyl)isothiazole (100) from 5-cyclopropyl-4- iodoisothiazole (101) by treatment with methylmagnesium bro- mide and 2-methylsulfonyl-4-trifluoromethylbenzoyl chloride (102).I F3C N + S 101 F3C N-Alkylisothiazolecarboxamides are synthesised from iodo- isothiazoles by treatment with CO and amines in the presence of palladium catalysts.89 Thus N-octyl-3-methylisothiazole-5-car- boxamide (103) was prepared by heating a 5-iodo-3-methyliso- thiazole (104) ± octylamine ± triphenylphosphine mixture in an atmosphere of CO (10 atm) in the presence of (PPh3)2PdCl2 (100 8C, 6 h).Me+Me(CH2)7NH2 N I S 104 Me(CH2)7NHC A convenient regiospecific method for the synthesis of iso- thiazole derivatives of the type 106 and 107 based on the reactions of thiazol-4-ylmagnesium bromide (prepared from 4-iodoisothia- zole (105) and ethylmagnesium bromide) with carbonyl com- pounds has been developed.90 679 Cl CO2Me MeONa N MeOH, 20 8C MeO S 97 (68%) C(O)N MeONa MeOH, 40 8C N S 98 C(O)N N SO2Me MeMgBr, THF, PhMe COCl 102 SO2Me O C N S 100 CO, (PPh3)2PdCl2 dioxane Me N O S 103680 R1CH(OH) R2=H N I S 106 1) EtMgBr 2) R1C(O)R2 N R1(O)C S 105 R2=OEt N S 107 R1=Ph, 4-ClC6H4, 2,4-Cl2C6H3, Ph; R2=H, OEt.For the first time, isothiazolyl gold(I) complexes were pre- pared by the reaction of isothiazol-5-yllithium with gold(I) chlor- ide or tetrahydrothiophene(pentafluorophenyl)gold; their protonation or alkylation gave the corresponding isothiazolinyli- dene complexes.91 b. Modification of amino, hydroxy, carboxy and other groups and functionalisation of the side chain in isothiazole derivatives In-depth studies into biological properties of functionalised iso- thiazoles carried out in the past decade were aimed at the develop- ment of methods for the synthesis of such compounds based on the known amino- and hydroxyisothiazoles, isothiazolecarboxylic acids and their chlorides, etc., and by functionalisation of the side chain.46 Heating of a 5-amino-4-chloro-3-methylisothiazole (108) ± (4-trifluoromethylphenyl)acetyl chloride (109) mixture in xylene gave N-isothiazol-5-ylamide 110.92 Me Cl 140 8C +F3CC6H4CH2COCl N H2N 109 S 108 Me Cl N F3CC6H4CH2C(O)HN S 110 A vast variety of novel useful N-isothiazol-5-ylamides have been prepared starting from structurally more complex acid chlorides and aminoisothiazoles containing various substituents in positions 3 and 4.92, 93 The methods for the synthesis of acylated 5-aminoisothiazoles of the type 111 and 112 have been developed.94 ± 96 R2 R3 O R3 R2 X O N N S R1 X N Y N R1 Z S 111 R4 112 R4 R1, R2, R3, R4=H, CN, NO2, CHO, alkyl, halogenoalkyl, alkoxyalkyl, alkoxy, alkylthio; X=alkylene, alkyleneoxy; Y, Z=O, S.For example, acylated 5-aminoisothiazole 113 was prepared from 4-chloro-5-[4-(4-cyanophenoxy)phenyl]acetylamino-3- methylisothiazole (114) by treatment with NaH in tetrahydro- furan and then with a twofold excess of allyloxycarbonyl chlor- ide.95 R V Kaberdin, V I Potkin Me Cl N HN 1) NaH, THF, 20 8C 2) ClCO2CH2CH CH2 3) H2O S C 4-NCC6H4OC6H4CH2 114 O O Me Cl C CHCH2O H2C N N S C 4-NCC6H4OC6H4CH2 113 O Carboxylic acids and acid chlorides of the isothiazole series are convenient starting compounds in the synthesis of isothi- azolecarboxamides.Thus a series of biologically active amides 116 have been synthesised from 3-methylisothiazole-5-carbonyl chlor- ide (115a) and 3,4-dichloroisothiazole-5-carbonyl chloride (115b) and various amines in the presence of triethylamine or pyri- dine.97 ± 101 R2 R1 Py or Et3N N +R3R4NH ClC(O) THF S 115a,b R2 R1 N R3R4NC(O) S 116 R1=H,R2=Me (115a); R1=R2=Cl (115b); R3=Ph, C6H5SO2, 4-ClC6H4, 1,2,4-triazolyl, pyrazolyl, piperazinyl; R4=H, Et. Amides 116 (R3=Het, R4=H) can be prepared by the reaction of 3,4-dichloroisothiazole-5-carboxamide with deriva- tives of the corresponding heterocylic compounds.101 5-Amino-3-methylisothiazole-4-carboxylic acid (117) is the starting compound in the synthesis of structurally more complex amides.Thus the reaction of the chloride 118 with 4-methylthio- aniline and subsequent acylation with acid chlorides yields 5-acyl- aminoisothiazole-4-carboxamides 119.102 Me Cl(O)C Me HO2C 1) 4-MeSC6H4NH2 2) RCOCl SOCl2 N N H2N H2N S 118 S 117 Me 4-MeSC6H4NH(O)C N RC(O)HN S 119 R=Me, Et, Ph. The reaction of 5-benzoylamino-3-methylisothiazole-4-car- boxylic acid (120) with p-chloroaniline in the presence of pyridine as the catalyst and alkoxycarbonyl chloride as the activating reagent gave 5-benzoylamino-3-methylisothiazole-4-carboxylic acid (121) p-chloroanilide.103 Me HO2C Py, ClCO2R +4-ClC6H4NH2 Me2CO EtOH N PhC(O)HN S 120Isothiazoles (1,2-thiazoles): synthesis, properties and applications Me 4-ClC6H4NH(O)C N PhC(O)HN S 121 (90%) R=Me, Et, Prn.3-Hydroxyisothiazole and its 4-halogeno derivatives react with acetals in the presence of toluene-p-sulfonic acid to give mixed acetals. For example, the reaction of isothiazole 77 with acetaldehyde dimethyl acetal results in 3-(1-methoxyethyloxy)iso- thiazole (122).104 Me OCH OH TsOH OMe +MeCH(OMe)2 N N 115 8C S 122 (23%) S 77 The reaction of 5-chloro-3-hydroxyisothiazole (123) with malonic dialdehyde bis(dimethylacetal) (124) in propionic acid yields a mixture of 5-chloro-3-(1,3,3-trimethoxypropyl)oxyiso- thiazole (125) and 1,3-bis(5-chloroisothiazol-3-yloxy)-1,3-dime- thoxypropane (126).105 OH EtCO2H N Cl +(MeO)2CHCH2CH(OMe)2 124 S 123 OCH(OMe)CH2CH(OMe)2 + N Cl S 125 OCH(OMe)CH2CH(OMe)O + N N Cl Cl 126 S S A great number of isothiazole derivatives of the general formula 127 have been prepared using a similar approach.OR O X1 Y Z(OR)2 N X2 127 S R=Alk(C17C18); X1=H, Br, Cl, Me; X2=H, Br, Cl; Y7Z=HC(CH2)nCH. 4,5-Disubstituted 3-hydroxyisothiazoles react with various allylic bromides to give alkenyl ethers of 3-hydroxyisothiazoles 128 ± 130.106 R5 O R1 R1 O O R4 N N R2 R2 R3 S S 129 128 O 681 O R1 N R2 Y S 130 R1, R2=H, Cl, alkyl(C1±C4); R3=H, alkyl, alkenyl, alkynyl, Ph, etc.; R4, various electron-withdrawing groups; R5=H, alkyl; Y=O, S, SO2.The condensation of isothiazole 77 and its 5-methylthio derivative 131 with arenesulfonyl chlorides 132 in the presence of a base yields the corresponding 3-arylsulfonyloxyisothiazoles 133.107 OH R2 + ClSO2 N R1 S 77, 131 132 R2 OSO2 N R1 133 S R1 = H (77), SMe (131); R2=H, 4-Me, 2-NO2, 4-NO2, 4-Br, 2-CO2Et. Aldehydes and ketones can be used for the functionalisation of isothiazoles. The reaction of the lithium derivative prepared by the metallation of 3-methyl-5-phenylisothiazole (134) with n-butyllithium in the presence of a lithium isopropyl- cyclohexylamide ±N,N,N0,N0-tetramethylenediamine system (LICA ±TMEDA) with carbonyl compounds leads to hydroxy derivatives 135.108 Me CH2CR1R2 OH BunLi N N +R1R2CO Ph Ph LICA7TMEDA S 135 S 134 R1=H,R2=Et, CH=CH2, Ph, CH=CHPh; R17R2 =(CH2)n, n=4, 5;R1=Ph; R2=Me, CH=CH2, Ph, CH=CHPh.The alkylation of a lithium derivative of isothiazole 134 with alkyl iodides or bromides gives compounds 136a ± c in up to 83% yields.109 Me CH2R 1) BunLi, LICA ±TMEDA 2) RX N N Ph Ph S 136a ± c S 134 R=Me, X = I (a); R=Bn, X=Br (b); R =Bu, X=Br (c). The condensation of 4-acetyl-5-chloro-3-methylisothiazole (137) with some aromatic and heterocyclic aldehydes involves the methyl group of the acetyl group rather than the methyl group in position 3 of the isothiazole ring to give a,b-unsaturated carbonyl compounds 138.110 Me RHC CH(O)C Me Ac B N N +RCHO Cl Cl S 138 S 137 R=2-ClC6H4, 4-ClC6H4, 4-Me2NC6H4, 2-furyl.682 (3-Chloro-4-cyanoisothiazol-5-yl)hydrazine (139) reacts with aromatic aldehydes to give the corresponding (3-chloro-4-cyano- isothiazol-5-yl)hydrazones 140.111 NC NC Cl Cl MeOH +ArCHO N N ArCH NHN H2NHN S 140 S 139 Ar=Ph, 4-O2NC6H4, 4-MeOC6H4, 4-ClC6H4, 2,4-Cl2C6H3, 3-O2NC6H4, 2,4-(O2N)2C6H3, 4-HOC6H4, 2-HOC6H4, 3-MeOC6H4, 2-MeOC6H4.Treatment of 4-cyano-3-hydroxy-5-methylthioisothiazole (141) with allyl bromide in the presence of potassium carbonate in DMF and subsequent treatment with iodine, potassium iodide and KOH yield the iodopropargyloxy derivative 142.112 Other cyanoisothiazole derivatives containing various alkyl, alkenyl and alkynyloxy(thio) groups in positions 3 and 5 were synthesised using a similar approach.112 OH NC 1) H2C=CHCH2Br, K2CO3, DMF 2) I2, KI, 10% KOH N MeS S 141 C I NC OCH2C N MeS S 142 (75%) 3,4-Dichloroisothiazole-5-carboxylic acid derivatives 143 (X=O, S; R is substituted alkyl, aryl and heterocyclic residues containing halogen, CN, NO2 , carbonyl, halogenalkylthio and other groups) have been synthesised recently from the acid chloride 115b.113 Cl Cl N C RX O S 143 4.Miscellaneous reactions for the synthesis of isothiazole The preparation of 3-substituted 4,5-diaminoisothiazoles used in the synthesis of novel heterocyclic systems (see Section III) is based on the conversions of 5-acetylamino-3-methyl-4-nitroiso- thiazole (144) which is readily obtainable from the commercially available 5-amino-3-methylisothiazole hydrochloride.114 Isothiazole 145 non-substituted in position 3 is formed upon oxidation of isothiazole 144 to carboxylic acid 146 and subsequent decarboxylation.Me O2N CrO3, H2SO4 N AcHN S 144 O2N CO2H O2N toluene, D N N AcHN AcHN S 145 S 146 4,5-Diaminoisothiazoles 147a,b are obtained from com- pounds 144 and 145 by deacetylation and reduction of the nitro group in the derivatives 148a,b.114 R V Kaberdin, V I Potkin R O2N NH3 N MeOH AcHN S 144, 145 R R H2N O2N Fe, HCl H2O, EtOH, D N N H2N H2N S 147a,b S 148a,b R=Me (a), H (b).5-(N-Alkylamino)-4-nitroisothiazoles 149a ± c were synthes- ised in high yields by the alkylation of sodium salts of 5-amino-4- nitroisothiazoles 148. The reduction of the nitro group in com- pounds 149a ± c gives 5-(N-alkylamino)-4-aminoisothiazoles 150a ± c.115 R1 O2N 1) NaH 2) R2X N H2N S 148 R1 R1 H2N O2N Fe HCl, EtOH, D N N R2HN R2HN S 149a ± c S 150a ± c R1=R2=Me (a); R1=H,R2=Me (b); R1=Me, R2=Bun (c). 4,5-Diamino-3-cyanoisothiazole (151) was obtained from 5-acetylamino-4-nitroisothiazole-3-carboxylic acid (146) in four steps which included the conversion of the carboxy group into the nitrile group and the reduction of the nitro derivative to diamine 151.115 CO2H O2N 1) SOCl2, D 2) NH3, MeOH N AcHN S 146 CONH2 O2N POCl3 85 8C N H2N S CN CN H2N O2N Fe HCl, EtOH, D N N H2N H2N S S 151 3-Acetamido-4-amino-5-(N-methylamino)isothiazole (152) is the starting compound in the synthesis of novel annelated hetero- cycles. This is prepared from ethyl 3-amino-5-(N-methylamino)- isothiazole-4-carboxylate (153) which is converted into the nitro derivative 154 in several steps. Selective removal of the acetyl protective group from the amino group in position 5 by treatment with methanolic ammonia and subsequent reduction of the 3-acetamido-5-(N-methylamino)-4-nitroisothiazole (155) formed completes the synthetic scheme.115, 116 NH2 HO2C NH2 EtO2C 1) KOH, D 2) HCl 1) H2O, D 2) Ac2O N N MeHN MeHN S S 153Isothiazoles (1,2-thiazoles): synthesis, properties and applications NHAc HNO3, TsOH CH2Cl2 N AcN S Me NHAc O2N NH3, MeOH N 0 8C AcNMe S 154 NHAc NHAc H2N O2N Fe N N HCl, EtOH, D MeHN MeHN S 152 S 155 4-Dibromoaminoisothiazoles 156a ± c used in the synthesis of the bisisothiazolopyrazine system are prepared by the reaction of with 157a ± c 4-aminoisothiazoles dibromoisocyanuric acid.117 ± 119 Br R2 R2 Br2N H2N N N Br N O N N R1 R1 S 156a ± c S 157a ± c R1=Br: R2=Me (a), Ph (b); R1=R2=Cl (c).A procedure for the synthesis of 3,4-dichloro-5-cyanoisothia- zole by the chlorination of the reaction product of carbon disulfide with NaCN in DMF120 has been improved.121 3,4-Dichloro-5- cyanoisothiazole synthesised (yield *88%) was converted into 3,4-dichloroisothiazole-5-carboxylic acid, which is employed in the synthesis of efficient plant growth regulators.Analogously, 3,5-dichloroisothiazole-4-carboxylic acid was prepared from 3,5- dichloro-4-cyanoisothiazole.122 4,5-Dichloroisothiazole-3-carboxylic acid (158) was prepared by hydrolysis of the trichloromethyl group of 4,5-dichloro-3- trichloromethylisothiazole (18) with fuming nitric acid and sub- sequent treatment of the reaction mixture with water.56 Cl Cl CO2H CCl3 1) HNO3 2) H2O N N Cl Cl S 158 (92%) S 18 The direction of reduction of the isothiazole 18 depends on the nature of the reducing agent.Boiling with zinc powder in ethanol results in the partial reduction of the trichloromethyl group and the formation of 4,5-dichloro-3-dichloromethylisothiazole (159). When tin dichloride is used, isothiazole 18 undergoes dechlorodi- merisation resulting in 1,2-bis(4,5-dichloroisothiazol-3-yl)tetra- chloroethane (160) in high yield.56 Cl CHCl2 Zn EtOH N Cl CCl3 Cl S 159 (53%) N Cl Cl CCl2 S 18 SnCl2 N Cl 2 S 160 The oxidation of 3-alkoxy-5-alkyl-4-cyanothioisothiazoles 161 under the action of Oxone (2KHSO3 .KHSO4 .K2SO4) 683 involves selectively the exocylic sulfur atom and affords the corresponding 5-alkylsulfonylisothiazoles 162 in high yields.123, 124 NC NC OR2 OR2 Oxone H2SO4 N N R1S R1O2S S 162 S 161 R1, R2=H, C17C12-alkyl, C27C7-alkenyl, C37C7-alkynyl, C37C7-cycloalkyl, Ph, PhO.The oxidation of the methylene group in substituted acet- amide 163 by dimethylformamide dimethylacetal (164), which can be regarded as a variant of the condensation reaction associated with the elimination of two MeOH molecules, gives enamino ketone 165.125 Me Cl O Me2NCH(OMe)2 164 N C 4-F3CC6H4O CH2 S NH 163 Me Cl O N C C 4-F3CC6H4O S NH CHNMe2 165 The chlorination of 5-[2-(N-tert-butyldimethylsilylamino)vi- nyl]isothiazoles 166 with N-chlorosuccinimide (NCS) proceeds selectively at the vinyl group resulting in the Z-isomers of isothiazole 167.126 R R R R NCS N N ButMe2SiHN ButMe2SiHN S 166 S 167 Cl R=4-ClC6H4, Ph.The monochlorination of related compounds with N-chloro- succinimide also proceeds in a selective manner. Isothiazoles 168 and 169 react with AgO3SCF3 to give dimeric silver(I) complexes the isothiazole fragment in which is linked to the metal centre through the nitrogen atom.127 Me Me N N N CH R(CH2)n (CH2)nN S 168 S 169 n=1, 2. R=[Et2N(CH2)2]2N, n=1; R=MeS, n=2. Treatment of selenolo[2,3-d ]isothiazole (170) with methyl- lithium yields a mixture of compounds including isothiazole 171.128 S S N CH MeSeHC MeLi N Se 171 170 Treatment of 5-substituted 4,5-dihydro-3-ethoxycarbonyliso- thiazolo[4,3-d ]pyrimidin-7(6H)-ones with hydrazine is accompa- nied by the opening of the dihydropyrimidinone ring and the formation of 4-amino-3-carbamoyl-5-hydrazinocarbonylisothia- zole (172).129684 CONH2 H2N N H2NNHCO S 172 It is of note that the ring opening reactions in bicylic isothiazole derivatives described above present purely theoretical interest.The reactions of 3,7-dichlorodiisothiazolo[4,5-b : 4050-e]pyr- azine (173) with benzylamine, aniline and morpholine are accom- panied by the opening of the pyrazine ring to give N,N0-bis- (5-amino-3-chloroisothiazol-4-yl)diazenes (174a ± c). The reac- tion of compound 173 with benzylamine gives 3,7-bis(benzyl- amino)bisisothiazolo[4,5-b : 4050-e]pyrazine (yield 5%) as a side product.130 Cl NR1R2 Cl N S HNR1R2 N S N N N N S N S Cl N 173 Cl NR1R2 174a ± c R1=H,R2=Bn (a, 25%); R1=H,R2=Ph (b, 25%); R17R2=(CH2)2O(CH2)2 (c, 28%).A mechanistic scheme for the synthesis of compounds 174a ± c has been proposed. Its first step consists in the addition of the amine at the C=N bond of the pyrazine ring. Interestingly, the reaction of compound 173 with MeONa in MeOH results in 5,6- dimethoxy-3-chloroisothiazolo[4,5-b]pyrazine, i.e., in the opening of one of the isothiazole rings. The difference in the behaviour of compound 173 in the reaction with the alkoxide anion and amines is explained by the difference in their basicities as well as by the presence of a mobile hydrogen atom in the amines which ensures their addition at the multiple bonds of the pyrazine ring.130 5. Synthesis of isothiazole 1,1-dioxides Methods for the synthesis, reactions and biological properties of isothiazole 1,1-dioxides were reviewed in 1997.131 Here we con- sider only the most recent publications.Thus a novel procedure for the synthesis of 4-amino-3,3-dimethyl-2,3-dihydroisothiazole 1,1-dioxide derivatives 175 based on substituted N-benzyl-N- sulfonylaminonitriles 176 has been developed recently. The cycli- sation was performed by treatment with sodium hydride in acetonitrile.132 Me H2N Me2C N SO2CH2R NaH X MeCN MeCH2 NC CH2C6H4X N R S 176 O O 175 (43% ± 75%) R=H, Me, Ph; X=H, 4-Cl, 3-Cl. Other 4-amino-2,3-dihydroisothiazole 1,1-dioxide deriva- tives,133 particularly compounds containing a cyano group in position 5, were prepared using analogous methods.134 ± 136 In the presence of bases, phenylmethanesulfonamide (177) reacts with dimethyl oxalate to give 4-hydroxy-5-phenylisothia- zol-3(2H)-one 1,1-dioxide (178).It is assumed that the linear methyl N-(benzylsulfonyl)oxalamidate 179, which is formed first, undergoes further cyclisation. A complex of dioxide 178 with DMF has been prepared.137 O ButONa, ButOH PhCH2SNH2+MeO2CCO2Me 7MeOH 177 O R V Kaberdin, V I Potkin O HO PhCH2SO2NHCCO2Me NH Ph O S 179 O O178 (55%) 6. Synthesis of dihydroisothiazolones Among representatives of this group, dihydroisothiazol-3-ones possessing high biological activities hold the greatest interest. The data on these compounds are summarised in the review.138 Some novel data on the synthesis of dihydroisothiazolones have been published recently.Thus the chlorination of 2-(N- methylcarbamoyl)ethanethiol (180) or bis[2-(N-methylcarb- amoyl)ethyl] disulfide (181) gave a mixture of 2,3-dihydro-2- methylisothiazol-3-one (182) and 5-chloro-2,3-dihydro-2-methyl- isothiazol-3-one (183).139 O O HSCH2CH2CONHMe Cl2 180 NMe NMe + Cl 5 ±20 8C (SCH2CH2CONHMe)2 S 183 S 182 181 Isothiazol-3-ones 182 and 183 can also be prepared by treat- ment of compounds 180 and 181 with thionyl chloride.140, 141 5-Chloro-2,3-dihydro-2-octylisothiazol-3-one (184) was syn- thesised by treatment of disulfide 185 with SO2Cl2.142 O SO2Cl2 NC8H17 Cl (C8H17NHCOCH2CH2S)2 185 S 184 The clathrate of compound 184 containing four molecules of 4,40-dihydroxydiphenylmethane manifests increased solubility in water. A procedure for the synthesis of isothiazol-3-one derivatives 187 from 3-alkylthio-2-cyano-3-mercaptoacrylamides 186 has been developed.143 O NC SR2 NC Cl2 or SO2Cl2 C C NR1 R2S R1NH(O)C SH S 187 186 R1, R2=H, lower alkyl, alkenyl, alkynyl, aryl, aralkyl, hetarylalkyl.The synthesis of isothiazol-3-ones devoid of highly toxic and carcinogenic nitrosoamines has been described in a patent. 144 III. Chemical transformations of isothiazoles Isothiazoles manifest aromatic properties and enter into the same reactions as other heteroaromatic compounds. Ring opening and transformations of the isothiazole ring, which give either func- tionalised alkenes or other heterocyclic compounds, deserve special attention.Addition reactions of isothiazoles leading to novel bisheterocyclic structures containing an isothiazole frag- ment are especially attractive. Oxidation reactions of the sulfur atom of the isothiazole ring yield reactive dioxides and present significant interest.64 1. Condensation reactions In recent years, isothiazole derivatives were used as starting compounds for the synthesis of several novel bicyclic compounds. Thus the reaction of 4,5-diamino-3-methylisothiazole (147a) with diethoxymethyl acetate affords 3-methylimidazo[4,5-d ]- isothiazole (188a) in low yield. Unsubstituted imidazo[4,5-d ]iso-Isothiazoles (1,2-thiazoles): synthesis, properties and applications thiazole could not be prepared from compound 147b.114 Isothia- zoles 147a,b easily undergo cyclisation with thiocarbonyldiimida- zole (189) to give unstable thiones 190a,b which are methylated in situ in alkaline media under the action of Me2SO4 to give 5-methylthioimidazo[4,5-d ]isothiazoles (191a,b) in good yields.Sodium salts of thiones 190a,b are also alkylated by benzyl and allyl bromides to give the corresponding imidazo[4,5-d ]iso- thiazoles 191c ± f in preparative yields.114, 115 Me H2N N H2N S 147a R1 H2N N H2N S 147a,bHN S NH 190a,b R1=R2=Me (191a); R1=H,R2=Me (191b); R1=Me, R2=Bn (191c) ; R1=Me, R2=All (191d); R1=H,R2 =Bn (191e); R1=H,R2=All (191f). 6-Alkyl-5-methylthioimidazo[4,5-d ]isothiazoles 192a ± c were prepared by treatment of 5-(N-alkylamino)-4-aminoisothiazoles 150a ± c with thiocarbonyldiimidazole (189) and subsequent methylation.The reactions of isothiazoles 150a,c with dieth- oxymethyl acetate result in compounds 193a,c.115 H2N R2HN S 150a ± c (EtO)2CHOAc 150a,c MeOCH2CH2OH R1=R2=Me (a); R1=H,R2=Me (b); R1=Me, R2=Bun (c). 3-Amino-6-methyl-5-methylthioimidazo[4,5-d ]isothiazole (192d) was obtained in good yield by successive treatment of 3-acetamido-4-amino-5-(N-methylamino)isothiazole (152) with thiocarbonyldiimidazole (189) and dimethyl sulfate.115 NHAc H2N N MeHN S 152 N MeS Me N Me N (EtO)2CHOAc N MeOCH2CH2OH S HN 188a N N C NH HN S 189 THF R1 R1 N 1) NaOH 2) Me2SO4 or R2Br N R2S N S S NH 191a ± f R1 R1 N 1) 189 2) NaOH 3) Me2SO4 N MeS N S RN2 192a ± c R1 N N S RN2 193a,c 1) 189, dioxane 2) NaOH 3) Me2SO4 NHAc NH2 N NH3 N MeS N MeOH, 100 8C S S Me N 192d 685 It should be noted, however, that not all 4,5-diamino-3-R- isothiazoles yield annelated products.Thus isothiazole 151 con- taining a cyano group in position 3 does not react with either diethoxymethyl acetate or thiocarbonyldiimidazole.115 Two approaches to the synthesis of 3,7-disubstituted bisiso- thiazolo[4,5-b:40,50-e]pyrazines 193a ± c, the first compounds con- taining a novel heterocyclic system, have been proposed.117 ± 119 It was found that the reaction of 3,5-dichloro-4-dibromoaminoiso- thiazole (156c) with a Cu(0) ± collidine system affords 3,7-di- chlorodiisothiazolo[4,5-b:40,50-e]pyrazine (193c) in 67% yield.117 Zlotin et al.118 suggested that this reaction has a radical character and studied the effect of UV light on isothiazoles 156a ± c. Irradiation of compounds 156a,c with a mercury lamp results in the cleavage of the N7Br bond and the formation of radicals 194a,c; their further transformations depend on the nature of the solvent used. Thus in dichloromethane, isothiazole 156c is con- verted into 4-amino-3,5-dichloroisothiazole virtually completely (157c). In CCl4, 3,7-disubstituted diisothiazolo[4,5-b:40,50-e]pyr- azines 193a,c (yields 58% and 76%, respectively) are the main reaction products of compounds 156a,c; their formation seems to proceed via the intermediate compounds 195a,c.N,N0-Di(iso- thiazol-4-yl)diazenes 196a,c (yields 37% and 13%, respectively) were identified as the side products.118 BrN R2 R2 Br2N hn N N 7Br R1 R1 S 194a ± c S 156a ± c Cl H2N R1=R2=Cl CH2Cl2 N Cl S 157c N N R2 R2 CCl4 N N R1 R1 7Br2 S S 196a ± c R2 R2 Br2N N CCl4, Br. N S N 7[R1] S Br R1 195a ± c 7Br, [7R1] ,7Br2 hn R2 N S N N S R2 N 193a ± c R1=Br, R2=Me (a), Ph (b); R1=R2=Cl (c). 5-Bromo-4-dibromoamino-3-phenylisothiazole (156b) mani- fests a similar behaviour upon irradiation with UV light; 3,7- diphenyldiisothiazolo[4,5-b : 40,50-e]pyrazine (193b) and N,N0- bis(5-bromo-3-phenylisothiazol-4-yl)diazene (196b) are the main reaction products.119 The isothiazolium salt 197 is condensed with cyclopenta- dienyl-, tert-butylcyclopentadienyl- and di-tert-butylcyclopenta- dienyllithium to give thialenes 198.145686 R2 MeNH R3 R1 Cl NC Li NC R1 + R2 NMe Ph S Ph FSO¡3R3 S 197 198 R1=R2=R3=H;R1=But, R2=R3=H; R1=R3=H,R2=But; R1=R3=But, R2=H.Reactivities of certain isothiazole 1,1-dioxide derivatives have been studied.146 It was found that 3-diethylamino-4-(4-meth- oxyphenyl)isothiazole 1,1-dioxide (199) reacts with sodium azide in ethanol to give a mixture of dihydroisothiazole oxides 200 and 201 and isothiazolotriazoles 202 and 203 in a ratio 72 : 12 : 9 : 7.146 NEt2 4-MeOC6H4 NaN3 N EtOH S O O 199 EtO EtO SO2 N SO2 N + +4-MeOC6H4 4-MeOC6H4 NEt2 NEt2 201 200 NEt2 4-MeOH4C6 N N N H N HN SO2 H SO2 N N + + O2S C6H4OMe-4 N N 4-MeOH4C6 NEt2 202 203 NEt2 Cycloaddition of the dioxide 199 to arylalkyl and aryl azides results inN-arylalkyl- orN-arylthiadiazabicyclo[3.1.0]hexene 204.The unstable cycloadducts 205, which are formed first (in some cases, they were isolated from the reaction mixture), easily eliminate the nitrogen molecule. H H SO2N RN RN3 SO2 N 199 RN N 7N2 NEt2 4-MeOH4C6 NEt2 204a ± e N 4-MeOH4C6 205 R=Ph (a), Bn (b), PhCH2CH2 (c), 4-MeOC6H4 (d), 4-O2NC6H4 (e). Thermal rearrangement of N-aryl- and N-phenyl-substituted bicyclic compounds 204a,c ± e affords 1,2-thiazete 1,1-dioxides 206a,c ± e, 1,2,6-thiadiazine 1,1-dioxides 207a,c ± e and pyrazole derivatives 208a,c ± e.Under optimum conditions, compound 207a was isolated in 51% yield. If the aziridine nitrogen atom has a benzyl substituent (com- pound 204b), the reaction follows a different route to afford the thiadiazine derivative 207b and pyrimidine 209.147 NR H RN SO2 4-MeOH4C6 SO2 N 4-MeOH4C6 N NEt2 Et2N 207a ± e 206a,c ± e R V Kaberdin, V I Potkin Ph N NR N N 4-MeOH4C6 4-MeOH4C6 209 208a,c ± e NEt2 NEt2 R=Ph (a), Bn (b), PhCH2CH2 (c), 4-MeOC6H4 (d), 4-O2NC6H4 (e). 4-Aryl-3-diethylamino-5-R-isothiazole 1,1-dioxides enter into cycloaddition reactions with diazoalkanes to give bicyclic com- pounds 210 with high regio- and stereoselectivity.The reaction with diazomethane yields a mixture of tautomeric pyrazolines 210 (R1=R2=H) and 211. Thermolysis of compounds 210 and 211 follows two routes. The loss of the nitrogen molecule leads to 2-thia-3-azabicyclo[3.1.0]hex-3-ene 2,2-dioxides 212. Elimination of SO2 and diethylcyanamide from the cycloaddition products results in the corresponding pyrazoles.148 R2 R3 R3 R3 R1 R1 SO2 N SO2 N SO2 N N N R2 N HN Ar Ar Ar NEt2 NEt2 NEt2 212 211 210 R1=R2=H, Me; R1=H,R2=CO2Et; R3=H, Me, Ph; Ar=Ph, 4-MeC6H4, 4-MeOC6H4. The readily available dioxide 199 enters into cyclocondensa- tion reactions with oxazolones 213a ± e and munchnones 214a ± h, which are prepared by cyclisation of (N-aroylamino)arylacetic acids 215a,b.149 The reactions with compounds 215a afford 4,6-diaryl-3-dieth- ylamino-3a,4-dihydro-3a-(4-methoxyphenyl)-6aH-pyrrolo[3,4-d ]- isothiazole 1,1-dioxides (216a ± e) (yields 60%± 74%) and their isomers 217a ± d (yields 5%± 13%).4,6-Diaryl-3-diethylamino- 3a-(4-methoxyphenyl)-5-methyl-3a-4-dihydropyrrolo[3,4-d ]iso- thiazole 1,1-dioxides 218a ± h are the main products in the reaction with munchnones 214a ± h.149 HO O O Ac2O toluene, 80 8C Ar2 Ar1 HN 215a SO2 N O 4-MeOH4C6 O 199 NEt2 7 Ar2 Ar1 HN + 213a ± e Ar2 H H Ar2 H SO2 N SO2 N N N + Ar1 NEt2 NEt2 Ar1 4-MeOH4C6 217a ± d H 4-MeOH4C6 216a ± e Ar2 Ar1 Compounds 216, 217 Ph Ph 4-ClC6H4 Ph 4-MeC6H4 Ph 4-ClC6H4 Ph 4-MeC6H4 Ph abcde687 Isothiazoles (1,2-thiazoles): synthesis, properties and applications HO O O Ac2O triethylamine result in the elimination of sulfur and recyclisation resulting in pyrrole-2-carboxylic acid derivatives 223.151 toluene, 80 8C Ar2 Ar1 R4 R3 R3 R2 Me N Et3N 215b X7 SO2 7S 7 R2 R1 R4 N R1H2C O 4-MeOH4C6 HN O N+S 222 199 NEt2 223 Ar2 Ar1 Me +N R1=CO2Me, CO2Et, CN; R2=H, Me, Ph; R3=H, Ph, 2-MeC6H4, 4-FC6H4, CO2Et; 214a ± h NMe; X=Cl, Br.R4 =Ph, N O, NHPh, SMe, 4-ClC6H4, N Ar2 SO2 N MeN Aminopyrroles 224 were obtained from isothiazolium salts 225 in a similar way (yields 70%± 90%).152 R4 Ar1 NEt2 N R3 R3 R2 R5 B X7 R4 H 4-MeOH4C6 218a ± h (63% ± 91%) R2 R1 N R1H2C Ar2 Ar2 Ar1 NH R5 N+S 225 224 Com- pound 218 Com- Ar1 pound 218 R1=H, alkenyl, aryl, NO2; R2, R3=H, substituted or unsubstituted alkyl, Ar, HetAr; R4, R5=H, heterosubstituted aryl or alkyl; X=Hal, ClO¡4 , BF¡4 , HSO¡4 , SO24 ¡, OH7, CF3SO¡3 .Ph 4-MeC6H4 Ph efg 4-MeOC6H4 h abcd Ph Ph 4-MeC6H4 Ph 4-MeOC6H4 Ph Ph Ph Ph 4-FC6H4 4-BrC6H4 4-NO2C6H4 The mechanism of formation of 3-aminopyrrole derivatives in the desulfurisation of isothiazolium salts has been studied.153 It was found that pyrrole 226 is formed from the salt 227 by a cascade of reactions via thioamide 228.153 C6H4Cl-4 + The cycloadducts 216 and 218 are decomposed at elevated temperatures or in alkaline media with the elimination of SO2 and diethylcyanamide to give 2,3,5-triarylpyrroles 219 and 1-methyl- 2,3,5-triarylpyrroles 220, respectively.149 4-MeOC6H4 Br7 H2N(O)CCH2N N S DBU 216 O 227 Ar2 Ar1 HN C6H4Cl-4 O N 4-ClH4C6 219 C6H4OMe-4 H2N(O)CH N N CONH2 S 180 ± 220 8C 218 HN O Ar1 Ar2 226 228 Me N 220 DBU, diazabicycloundecene.A convenient procedure for the synthesis of 2-phenylthiocar- bonylmethylidenedihydrothiazole derivatives 229 from isothiazo- lium chlorides has been developed.154 R1 R2 R2 S NaBH4 PhC(S)HC 4-Amino-3-carbamoyl-5-(ethoxycarbonyl)isothiazole is used in the synthesis of the isothiazolo[4,5-d ]pyrimidine derivatives 221.150 NH2(O)C CHCl3, EtOH +N Ph R3 N S R3 229 HN Cl7 N N N CH C6H4R S R1=Ac, EtCO; R2=CO2Et, CO2Me; R3=Me, Et.221 R=2-OMe, 2-Cl, 3-Br, 3-NO2. 2. Ring transformation reactions N-Arylisothiazolium salts 230 containing an activated methyl group in position 5 dimerise into thiadiazapentalenes 231 upon treatment with a base. The sulfur atom of one molecule of the salt is attacked by an activated methyl group of another molecule to give the intermediates 232. Subsequent oxidative closure of the ring via zwitterionic intermediates 233 results in thienothiadiaza- pentalenes 231. A competing reaction gives 5-(2-thienyl)isothia- zolium salts 234 with elimination of aniline.155 In recent years, some readily available isothiazolium salts have been used in the synthesis of other heterocyclic compounds, pyrrole derivatives, in particular.Thus the reactions of N-alkoxy- carbonylmethyl- and N-cyanomethylisothiazolium 222 salts with688 Me B +N Me Ar S X7 230 Ar N7 Me S Me Me 233 Me 72H Me Me 7ArNH2 Me Ar=Ph, 4-MeC6H4; X = Cl7, ClO¡4 ; B=(cyclo-C6H11)2NH. The reaction between the salts 230 and 235 catalysed by dicyclohexylamine in methanol or DMSO yields `mixed' thiadia- zapentalenes 236 upon oxidative cyclisation and salts 237 upon elimination of aniline.156, 157 Me + +N Me S Ar1 ClO¡4230 Ar2 N S S 236 Ar1=Ph, 4-MeC6H4; Ar2=Ph, 4-MeC6H4, 4-MeOC6H4. Photochemical reactions of several isothiazoles have been studied. Irradiation of 4-phenylisothiazole in benzene yielded small amounts of 4-phenylthiazole (238).When the photolysis was carried out in the presence of triethylamine, this rearrange- ment becomes predominant.158 Ph Ph hn N Et3N S H The effect of triethylamine and the solvent polarity on the photochemical reaction of 5-phenylisothiazole (239) has been studied.159 It was found that irradiation in the absence of triethyl- amine gives 4-phenylthiazole (238) as the main product (yield 15%). Other reaction products are represented by 3-phenyliso- thiazole (240) and 2-phenylthiazole (241). In the presence of Et3N, 5-phenylthiazole (242) is the main product (yield 14%). Ar N Me S Me S X7 +N Ar 232 Me Ar S +N Ar Ar N N S S Me 231 Ar S +N X7 S 234 Me (cyclo-C6H11)2NH N+ Ar2 S ClO¡4235 Ar1 Ar1 ClO¡4S +N N + Me S Me 237 Ph C7 N +N S SH 238 R V Kaberdin, V I Potkin Irradiation of 5-phenylisothiazole (239) in polar solvents makes this rearrangement more regioselective. The photolysis in methanol in the presence of Et3Ngives exclusively compounds 238 and 242 (yields 9% and 34%, respectively).In a more polar solvent (e.g., 2,2,2-trifluoroethanol), only thiazole 241 was iden- tified in the reaction mixture; in the presence and in the absence of Et3N, its yield was 42% and 32%, respectively.159 Ph Ph N N hn PhH + N + Ph S S S 241 240 238 N Ph N S 239 hn PhH, Et3N +238+240 Ph S 242 3. Ring opening reactions Under conditions of phase-transfer catalysis [PhH, H2O, tris(2,6- dioxaheptyl)amine], the reaction of 3,5-dimethylisothiazole (243) with acetylcobalttetracarbonyl generated in situ from Co2(CO)8 , CO and MeI is accompanied by ring opening and N-acylation, resulting in thione (244) (the ratio of the E- and Z-isomers is equal to 1 : 10).160 Me AcCo(CO)4 C(Me)NHCOMe (Me)C(S)CH N Me 244 (61%) S 243 Other N-acylated unsaturated thiones are synthesised from isothiazoles in a similar way.A convenient procedure has been developed for the synthesis of phenylthiocarbonylketene S,N-acetals (246) based on the reaction of 2-alkyl-3-alkylthio-5-phenylisothiazolium salts (e.g., the salts 245) with sodium borohydride.161 SEt SEt NaBH4 C PhC(S)HC Ph Me NHMe 246 I7 +N S 245 The reaction of 3-diethylamino-4-(4-methoxyphenyl)isothia- zole 1,1-dioxide (199) with organomagnesium compounds inTHF occurs via ring opening leading to a mixture of E- and Z-isomers of 3-substituted 2-arylpropeneamidines 247.162 NEt2 4-MeOC6H4 NH R 1) RMgBr, THF 2) H2O N C C C S H O O NEt2 C6H4OMe-4 247 199 R=Me, Et, Ph, HC C, MeC C, PhC C.The chemistry of the 4-nitroisothiazole-5(2H)-imine deriva- tives 248, particularly, their isomerisation and desulfurisation, has been discussed in the papers 163, 164 and a recent review.165 NO2 NAr ArN S 248 It has already been noted (Section III.2) that the photolysis of 4-phenylisothiazole in benzene gives small amounts of 4-phenyl- thiazole (238) as a result of a rearrangement; cyanothiol 249,689 Isothiazoles (1,2-thiazoles): synthesis, properties and applications which was trapped as benzyl sulfide 250, is the main photolysis product in the absence of a base.158 Ph reaction with 2,4,6-triethylbenzonitrile oxide to give the dihydro- isoxazole derivative 260.169 NEt2 4-MeOC6H4 CN Ph CN Ph 2,4,6-Et3C6H2CNO BnBr hn, PhH NH N C H2C S S SBn H SH H O 250 249 EtO O259 NEt2 4-MeOC6H4 4.Miscellaneous reactions of isothiazole derivatives The oxidation of 4,5-disubstituted isothiazoles with hydrogen N O NH S O 2,4,6-Et3C6H2 peroxide results in the corresponding isothiazol-3(2H)-one 1,1- dioxides 251.166 R1 O R1 H2O2 N NH AcOH R2 R2 S S O O251 OEt O 260 2,6-Dichlorobenzonitrile oxide reacts with isothiazolone (261a) at the double bond to give isoxazolecarboxanilide (262) as a result of transformation of the primary cycloadducts formed.Contrary to expectations, 2,4,6-triethylbenzonitrile oxide adds to the exocyclic carbonyl group of isothiazolone 261b to give the monoadduct 263 and the bisadduct 264.170 R1=Me, Ph, H; R2=Me, Ph, 4-BrC6H4, 4-MeOC6H4. PhHN(O)C O C6H3Cl2-2,6 Dioxides 253, 254 are the oxidation products of the isothiazo- lium salts 252.167 N NPh+2,6-Cl2C6H3CNO R R O Me R O 262 S 261a X7 OOH O N N Ar Me Ar Ar S S 2,4,6-Et3C6H2CNO O O NPh O O +N S 252 PhC(O) 254 253 S 261b R=Alk, Ph. 2,4,6-Et3C6H2 O O N Ph O NPh O NPh + N S O S Ph O 5-Bromo-3-diethylamino-4-(4-methoxyphenyl)-2,3-dihydro- isothiazole 1,1-dioxide (255) reacts smoothly with various organo- tin compounds in the presence of palladium catalysts to yield the corresponding 5-substituted derivatives 256.168NEt2 4-MeOC6H4 NEt2 4-MeOC6H4 O N 263 2,4,6-Et3C6H2 R4Sn NH NH 264 C6H2Et3-2,4,6 R Br S S O O O O 256 255 R=CH2=CH, Ph, HetAr, Ar. An efficient approach based on the Michaelis reaction is used in the synthesis of 5-substituted 3-amino-4-arylisothiazole 1,1- dioxides and their 4,5-dihydro derivatives.The addition of thiols, alcohols and trifluoroacetamide to 3-diethylamino-4-(4-meth- oxyphenyl)isothiazole 1,1-dioxide (199) in the presence of bases NEt2 4-MeOC6H4 R1SH N The reaction of the vinyl derivative 256 with nitrile oxides yields the cycloadducts 257a ± e, which are rearranged into 4,5- dihydro-5-(isoxazol-5-yl)isothiazole 1,1-dioxides 258a ± e (an equimolar mixture of cis- and trans-isomers) upon heating in DMSO.169 R1S S NEt2 4-MeOC6H4 O O ArCNO 265 R1=Me, Ph, cyclo-C6H11.NH CH H2C S NEt2 4-MeOC6H4 NEt2 4-MeOC6H4 O R2OH O256 N R2ONa N S R2O NEt2 NEt2 4-MeOC6H4 4-MeOC6H4 S O O Ar Ar O O 199 D, DMSO N NH 266 S S N N R2=Me, Et, Pri. O O O O O 258a ± e O257a ± e NEt2 4-MeOC6H4 N CF3CONH2 K2CO3, MeCN TEBA7Cl CF3COHN Ar=3,5-Cl2-2,4,6-Et3C6 (a), 2,6-Cl2C6H3 (b), 4-ClC6H4 (c), 2,4,6-Et3C6H2 (d), 4-NO2C6H4 (e). S O O TEBA± Cl, triethylbenzylammonium chloride. 267 3-Diethylamino-2,3-dihydro-5-(1-ethoxyvinyl)-4-(4-methoxy- phenyl)isothiazole 1,1-dioxide (259) enters into the cycloaddition690 occurs regiospecifically and yields a mixture of (4S,5S)- and (4R,5S)-diastereomers of 5-substituted 4,5-dihydroisothiazole 1,1-dioxides 265 ± 267.171 The reaction of the 5-bromo-derivative 255 with thiols or amines gives the substituted products of the bromine atom 268 and 269.168 NEt2 4-MeOC6H4 R1SH B NH R1S S O O 268 4-MeOC6H4 NEt2 R1=H, Me, Ph, Bn, NH Br , 4-MeC6H4, S O O N farnesyl 255 NEt2 4-MeOC6H4 R1R2NH NH R1R2N S O O 269 R1=4-MeC6H4, R2=H; R1=R2=Me.IV. Areas of application of isothiazoles As noted above, isothiazole derivatives manifest a broad spectrum of useful properties.Back in 1967, isothiazoles were used as starting compounds in the synthesis of highly efficient penicillins and cephalosporins,2, 3 which gave a strong impetus to systematic studies of the biological properties of isothiazole derivatives. In 1988, Mel'nikov who studied the production and application of pesticides and plant growth regulators drew attention to the broad potentialities of isothiazole derivatives.172 Recent years have been marked by numerous publications (including patents and patent applications) devoted to various applications of isothiazoles as efficient agrochemical and medicinal agents. It was found that 4-benzoyl- and 4-(hetaroyl)isothiazole derivatives manifest herbicidal activities.85 ± 88, 173 There is evi- dence of the use of substituted isothiazole-5-carboxamides 270,174 isothiazolylpyridines 271 175 and dihydroisothiazolone derivatives as herbicides.176 R1 R2 N Z R2 N N S N R1 O S 270 271 R1=Hal, MeO, FCH2O, F3CO; R2=CN, CO2H, CHO.R1=H, (un)substituted alkyl, (un)substituted acyl; R2=(un)substituted aryl, hetaryl; Z=(un)substituted C1±C4-alkylene. When used as herbicides, isothiazole derivatives manifest synergistic effects and are included in various compositions. Thus compounds 272 are auxin transport inhibitors and are used together with other herbicides in order to enhance their action.10 ± 14 C(Me) NNHCONHC6H3-5R1-3R2 MO2C N 272 S R1, R2=H, F, Cl; M=H, Na. R V Kaberdin, V I Potkin The role of herbicides in these compositions is played by different compounds, e.g., dicamba, glifosat, 2,4-D10 and herbi- cides based on phenoxypropionic 11 and phenoxybutyric acids.14 Some isothiazoles manifest high insecticidal activities.These include 4,5-dihydro-1H-pyrazole derivatives containing various isothiazole substituents in position 4,177, 178 1,2,3-triazole deriva- tives containing isothiazole substituents in position 3 ,179 etc. The cyanoisothiazole derivatives 161 manifest high insecticidal activ- ities against termites.180 Many isothiazole derivatives, particularly acylated 5-amino- isothiazoles,94, 95 isothiazolecarboxamides,96 ± 98 4-cyanoisothia- zoles,112, 123, 124 3,4-dichloroisothiazole-5-carboxylic acid and its derivatives,121 etc., manifest fungicidal activities.(3-Methyliso- thiazol-5-yl)(2,6-dinitro-4-trifluoromethylphenyl)amine (273) is used as an agrochemical.181Me NO2 N S HNNO2 F3C 273 Many heterocyclic and aromatic compounds containing var- ious isothiazole residues 182, 183 and 3-isothiazolone deriva- tives 184 ± 189 in their side chains manifest high fungicidal activities. Isothiazolones are broad-spectrum biocides; they are included in various compositions including commercial ones. They hold great promise for the technology and agriculture being non-harmful to humans, animals and the environ- ment.20, 23, 30, 190 ± 197 Isothiazole and isothiazolone derivatives are used in photog- raphy,198 ± 212 cosmetics,213 ± 215 and as dyes;216 ± 218 besides, they are components of synergistic bactericidal preparations 219 ± 225 and are used in the chemiluminescent analysis 226, 227 of radio- graphic visualisation.228 Many of them are antifouling agents.229 ± 235 A great number of isothiazole derivatives manifest high antimicrobial activities and are widely used for the protection of natural and technical materials, plants and other objects from harmful microorganisms.These include 3-alkoxyisothiazoles (particularly, compound 122),104 allylic ethers 128 ± 130,106 5-ami- noisothiazoles,236 3,5-diaminoisothiazole derivatives 6,51 isothia- zolecarboxamides 101 and the derivatives 125 and 126.105 The overwhelming majority of compounds endowed with antimicrobial activities were found among isothiazolone deriva- tives.237 ± 265 It was found that the addition of even the simplest isothiazolones to various compositions, e.g., 2-methyl- or 5-chloro-2-methyl-2,3-dihydroisothiazol-3-one, increase mark- edly their activities.266 ± 271 Some isothiazole derivatives manifest different types of bio- logical activities.Thus acylated aminoisothiazoles (compounds 165 125, 272 and 274 273) are used as insecticides and acaricides. Me N O NC CH2C(O)NH S 274 Compositions possessing bactericidal and fungicidal proper- ties were prepared from some dihydroisothiazolones.274 Cyano- isothiazoles 112 are used as fungicides and bactericides. Compositions comprising aminoacrylamides and trisubstituted isothiazoles possess insecticidal, fungicidal and herbicidal activ- ities.275 Compounds 275 have been patented as nematocides, insecticides and acaricides.276Isothiazoles (1,2-thiazoles): synthesis, properties and applications R N S 275CHCH2CH2SOn , n=0±2.R=CF2 N-Isothiazol-5-ylamides (e.g., compound 110 92) manifest an even broader range of pesticidal activities and possess nematoci- dal, insecticidal, miticidal and fungicidal properties. An intense search for therapeutic agents among isothiazole derivatives has been carried out over the past decade. Cephalo- sporins containing a (4-carboxy-3-hydroxyisothiazol-5-yl)thio- methyl group in position 3 (276) are used as medicinal drugs possessing a broad spectrum of antibacterial activities, particu- larly with respect to gram-negative bacteria.277 NOCH(SR1)CO2R2 OH O¡2 C CONH N S Bun4 N+ N Ph3CHN S S S O CO2CH2 276 C6H4OMe-4 Isothiazolyl aminoalkyl ketones were patented as myorelax- ants.278 5-Carboxy-3-phenylisothiazoles, particularly 4-amino-3- (3-trifluoromethylphenyl)isothiazole-5-carboxylic acid (277), were recommended for use as antiinflammatory agents.279 ± 281 C6H4CF3-3 H2N N HO2C S 277 Dihydroisothiazol-3-one 1,1,-dioxide derivatives inhibit ser- ine proteases. They have been recommended for the treatment of various inflammatory diseases and as antimetastatic agents.7, 8 Some aromatic and heterocyclic compounds containing isothia- zole residues inhibit phosphodiesterase and are widely used in the clinical practice as antiasthmatic drugs and in the treatment of diabetes, hypertension, allergic rhinites, nephrites and other diseases.282, 283 Compounds 278 and their salts have been patented as effective agents for the treatment of Alzheimer's disease.4 R1 N R2 S 278 R1=H, alkyl, cycloalkyl, (un)substituted phenyl; R2=substituted pyrrolidinyl.Trisubstituted isothiazole derivatives containing an amino acid or cyclobutene fragment in position 3 were recommended for the treatment of brain ischemia, Huntington's and Parkinson's diseases, epilepsy, Alzheimer's disease, schizophrenia, stress, anxiety and various memory disorders.284 5-Hydrazinoisothiazole derivatives act as immunodepres- sants,285 whereas 3-isothiazolone derivatives are included in the composition of weight reduction drugs.286 They are also used for modification of the interleukin-5 receptor.287 The isothiazole ring is the constituent of various physiologi- cally active compounds.Thus heterocyclic derivatives of urea containing an isothiazole substituent act as antagonists of 5-HT2C and 5-HT2B receptors and are used in the preparation of anti- depressant drugs and in the treatment of Alzheimer's disease, schizophrenia, etc.288 Compound 279 is a highly efficient antag- 691 onist of 5-HT2B receptors, although its activity is not too high.289 ± 291 2-Amino-3-(3-hydroxy-5-methylisothiazol-4-yl)pro- pionic acid (280), the isothiazole analogue of 2-amino-3-(3- hydroxy-5-methylisoxazol-4-yl)propionic acid (281, AMPA), blocks the activation of glutamate receptors which are crucial for brain ischemia, Alzheimer's disease, hypoglycemia, etc.292, 293 O HO2C OH Me HN HN N H2NMe N S S 280 279 Me HO2C OH N H2NMe O 281 V. Conclusion As can be seen from the material presented above, new original methods for the synthesis of many isothiazole derivatives have been developed in recent years. These include some previously unknown heterocyclisation reactions (e.g., the syntheses based on a-amino ketones and 2-nitropentachloro-1,3-butadiene), the syn- theses of isothiazoles from other, more accessible heterocyclic compounds (particularly, the syntheses based on trithiatriazine trichloride) as well as the syntheses of previously unknown fluoro- substituted isothiazoles.Studies aimed at the functionalisation of isothiazoles, e.g., cross-coupling reactions which made possible the synthesis of previously unavailable derivatives (e.g., isothi- azoles containing two acetylene groups) have received further development. The syntheses of biologically active amides, isothia- zolones and highly reactive 1,1-dioxides have been carried out. Isothiazoles were used as starting materials for the synthesis of novel, previously unavailable biheterocyclic structures, such as imidazoisothiazoles, diisothiazolopyrazines, isothiazolotriazines, substituted pyrroloisothiazole 1,1-dioxides and other compounds. Methods for the synthesis of various heterocyclic compounds (pyrazoles, thiadiazapentalenes and other hardly accessible com- pounds) from readily available isothiazole derivatives have been developed.High biological activities of isothiazoles is the main impetus for conducting in-depth studies in the field of isothiazole chem- istry. More than 50% of work cited in this review are patents devoted to the synthesis and applications of isothiazoles as efficient agrochemical and medicinal preparations. Obviously, the exceptionally broad spectrum of useful proper- ties of isothiazoles determines the expediency of further studies into their chemistry. We hope that the present review will help attract more attention to this field of chemistry. References 1. A Adams, R Slask Chem. Ind. (London) 42 1232 (1956) 2. R Raap, R G Micetich J.Med. Chem. 11 70 (1968) 3. US P. 3 268 523; Chem. Abstr. 65 18 597 (1967) 4. US P. 5 409 946; Chem. Abstr. 123 55 872 (1995) 5. US P. 5 411 977; Ref. Zh. Khim. 06 O 76P (1997) 6. US P. 5 378 729; Chem. Abstr. 123 33643 (1995) 7. US P. 5 550 139; Ref. Zh. Khim. 07 O 152P (1999) 8. WO PCT 95 18 797; Chem. Abstr. 123 340 140 (1995) 9. L Matzen, A Engesgaard, B Ebert,M Didriksen, B Frolund, P Krogsgaard-Larsen, J W Jaroszewski J. Med. Chem. 40 520 (1997) 10. Austr. P. 670 809; Ref. Zh. Khim. 22 O 391P (1997) 11. US P. 5 681 793; Ref. Zh. Khim. 07 O 394P (2000) 12. US P. 5 888 931; Ref. Zh. Khim. 02 O 475P (2000) 13. US P. 5 888 932; Ref. Zh. Khim. 04 O 402P (2000)692 14. US P. 5 888 937; Ref. Zh. Khim. 11 O 431P (2000) 15. Jpn. Appl.04-270 203; Chem. Abstr. 118 75 364 (1993) 16. US P. 5 591 760; Ref. Zh. Khim. 01 O 255P (1998) 17. US P. 5 489 588; Ref. Zh. Khim. 02 O 379P (1998) 18. US P. 5 648 086; Ref. Zh. Khim. 23 O 385P (1998) 19. US P. 5 559 083; Ref. Zh. Khim. 12 O 426P (1999) 20. BRD Appl. 19 548 710; Chem. Abstr. 127 118 601 (1997) 21. US P. 5 661 119; Chem. Abstr. 127 222 242 (1997) 22. US P. 5 922 745; Ref. Zh. Khim. 14 O 380P (2000) 23. US P. 5 658 467; Chem. Abstr. 127 224 778 (1997) 24. US P. 5 188 663; Chem. Abstr. 119 88 937 (1993) 25. US P. 5 683 686; Ref. Zh. Khim. 17 O 402P (1999) 26. Jpn. Appl. 07-140 620; Chem. Abstr. 123 241 899 (1995) 27. Jpn. Appl. 09-211 786; Chem. Abstr. 127 255 264 (1997) 28. BRD Appl. 4 426 623; Chem. Abstr. 124 204 936 (1996) 29.Br. Appl. 2 335 924; Ref. Zh. Khim. 09 N 162P (2000) 30. T Mulligam Spec. Chem. 16 161 (1996); Ref. Zh. Khim. 05 O 282 (1997) 31. R Slack, K R H Wooldridge Adv. Heterocycl. Chem. 4 107 (1965) 32. K R H Wooldridge Adv. Heterocycl. Chem. 14 1 (1972) 33. M Hori, H Shimizu Sulfur Rep. 4 313 (1986) 34. D M McKinnon Sulfur Rep. 15 317 (1994) 35. B Iddon Heterocycles 41 533 (1995) 36. J W Pavlik Mol. Supramol. Photochem. (Organic Photochemistry) 1 57 (1997); Chem. Abstr. 128 204 460 (1998) 37. V P Litvinov Usp. Khim. 68 817 (1999) [Russ. Chem. Rev. 68 737 (1999)] 38. Th L Gilchrist J. Chem. Soc., Perkin Trans. 1 2849 (1999) 39. M F Ward Annu. Rep. Prog. Chem., Sect. B 95 157 (1999) 40. A R Katrizky, J Lagowski Heterocyclic Chemistry (New York: Wiley) (Translated from the English; Moscow: Izd.Inostr. Lit., 1963) 41. L A Paquette Principles of Modern Heterocyclic Chemistry (New York: Benjamin, 1968) 42. K Turnbull, in Heterocyclic Chemistry Vol. 5 (London: Wiley, 1986) 43. T L Gilchrist The Chemistry of Heterocyclic Compounds (Translated from the English; Moscow: Mir, 1996) 44. R F Chapman, B J Peart, in Comprehensive Heterocyclic Chemistry II Vol. 3 (Ed. I Shinkai) (Oxford: Elsevier, 1996) 45. P A Bradley,D J Wilkins Progress in Heterocyclic Chemistry Vol. 11 (Eds G W Gribble, T L Gilchrist) (Oxford: Pergamon Press, 1999) 46. Methoden der Organischen Chemie (Houben-Weyl) Bd. EVIII(III) (Stuttgart: Georg Thieme Verlag, 1993) 47. S D Sokolov Usp. Khim. 58 533 (1979) [Russ.Chem. Rev. 58 289 (1979)] 48. M M Kempbell, in Comprehensive Organic Chemistry (Eds D Barton, W D Ollis) (Oxford: Pergamon Press, 1979) Vol. 4 49. A Adams, R Slack J. Chem. Soc. 3061 (1959) 50. R E Hackler, K W Burow Jr, S V Kaster, D I Wickiser J. Heterocycl. Chem. 26 1575 (1989) 51. M T Cocco, C Congiu, A Maccioni, V Onnis, M L Schivo, A De Logu Farmaco 49 137 (1994); Chem. Abstr. 121 205 259 (1994) 52. Pol. P. 175 889; Ref. Zh. Khim. 01 O 17P (2000) 53. A Kunugi, Md A Jabbar, K Mori, H Uno Elecrochim. Acta 44 4583 (1999) 54. Eur. Appl. 1 053 680; Ref. Zh. Khim. 06 O 158P (2001) 55. R V Kaberdin, V I Potkin, Yu A Ol'dekop Dokl. Akad. Nauk SSSR 300 1133 (1988) a 56. R V Kaberdin, V I Potkin, Yu A Ol'dekop Zh. Org. Khim. 26 1560 (1990) b 57.A I Verenich, A A Govorova, N MGalitskii, V I Potkin, R V Kaberdin, Yu A Ol'dekop Khim. Geterotsikl. Soedin. 399 (1992) c 58. A N Akopyan, A M Saakyan, Z A Dzhauari Arm. Khim. Zh. 21 (5) 414 (1968) 59. M G Voronkov, N S Vyazankin, E N Deryagina Reaktsii Sery s Organicheskimi Soedineniyami (Reactions of Sulfur with Organic Compounds) (Novosibirsk: Nauka, 1979) 60. J N Bridson, S B Copp,M J Schriver, S G Zhu,M J Zaworotko Can. J. Chem. 72 1143 (1994) 61. J N Bridson,M J Schriver, S G Zhu Can. J. Chem. 73 212 (1995) 62. M M Krayushkin,M A Kalik, A Ya Kudryavtseva Izv. Akad. Nauk, Ser. Khim. 1892 (1992) d 63. D K Buffel, L Meerpoel, S M Toppet, G J Hoornaert Nucleosides Nucleotides 13 719 (1994); Chem. Abstr. 121 83 859 (1994) R V Kaberdin, V I Potkin 64.X-G Duan, X-L Duan, C W Rees J. Chem. Soc., Perkin Trans. 1 2831 (1997) 65. X-L Duan, Ch W Rees, T-Y Yue Chem. Commun. 367 (1997) 66. X-L Duan, R Perrins, Ch W Rees J. Chem. Soc., Perkin Trans. 1 1617 (1997) 67. Ch W Rees, T-Y Yue J. Chem. Soc., Perkin Trans. 1 2247 (1997) 68. S M Laaman, O Meth-Cohn, Ch W Rees Synthesis 757 (1999) 69. X-L Duan, Ch W Rees J. Chem. Soc., Perkin Trans. 1 3189 (1997) 70. K Hartke, A Kraska Arch. Pharm. 326 (1) 57 (1993); Chem. Abstr. 118 191 686 (1993) 71. B Schulze, U Dietrich, K Illgen, J Siler Zh. Org. Khim. 30 1379 (1994) b 72. B Schulze, G Kirsten, S Kirrbach, A Rahm, H Heimgartner Helv. Chim. Acta 74 1059 (1991) 73. S Kirrbakh, K Myetze, R Kempe, R Meizinger, A Kol'berg, B Schulze Zh.Org. Khim. 32 1745 (1996) b 74. O Miyato, S Yamakawa,K Muroya, T Naito Heterocycles 51 1513 (1999) 75. Bhavana, S Hastak, B J Ghiya Ind. J. Heterocycl. Chem. 2 133 (1992); Chem. Abstr. 118 212 952 (1993) 76. L Capuano, V Hammerer, V Huch Liebigs Ann. Chem. 23 (1994) 77. M R Bryce, S Yoshida, A S Batsanov, J A K Howard J. Chem. Soc., Perkin Trans. 1 1157 (1997) 78. K Emayan, R F English, P A Koutentis, Ch W Rees J. Chem. Soc., Perkin Trans. 1 3345 (1997) 79. D Clarke,K Emayan, Ch W Rees J. Chem. Soc., Perkin Trans. 1 77 (1998) 80. R B Woodword The Harvey Lecture Series 59 (New York: Academic Press, 1965) p. 31 81. S G Zlotin, P G Kislitsyn, O A Luk'yanov Izv. Akad. Nauk, Ser. Khim. 1887 (1997) d 82. S G Zlotin, P G Kislitsyn, O A Luk'yanov Izv.Akad. Nauk, Ser. Khim. 534 (1998) d 83. S G Zlotin, P G Kislitsyn, O A Luk'yanov Izv. Akad. Nauk, Ser. Khim. 537 (1998) d 84. V I Potkin, N I Nechai, R V Kaberdin Izv. Akad. Nauk Belarusi, Ser. Khim. Nauk (4) 85 (1994) 85. WO PCT 97 38 987; Chem. Abstr. 127 346 385 (1997) 86. WO PCT 97 38 996; Chem. Abstr. 127 346 386 (1997) 87. WO PCT 97 38 988; Chem. Abstr. 127 358 855 (1997) 88. BRD Appl. 19 614 859; Ref. Zh. Khim. 20 O 483P (1998) 89. Jpn. Appl. 07-196 637; Chem. Abstr. 124 8805 (1996) 90. F Guilloteau, L Miginiac Synth. Commun. 25 1383 (1995) 91. H G Raubenheimer,M Desmet, G J Kruger J. Chem. Soc., Dalton Trans. 2067 (1995) 92. WO PCT 95 31 448; Chem. Abstr. 124 202 240 (1996) 93. J G Samaritoni, L Arndt, T J Bruce, J E Dripps, J Gifford, C J Hatton, W H Hendrix, J R Schoonover, G W Johnson, V B Hegde, S Thornburgh J.Agric. Food. Chem. 45 1920 (1997); Chem. Abstr. 126 302 652 (1997) 94. BRD Appl. 19 542 372; Ref. Zh. Khim. 23 O 408P (1998) 95. BRD Appl. 19 736 545; Ref. Zh. Khim. 12 O 375P (2000) 96. BRD Appl. 4 328 425; Ref. Zh. Khim. 14 O 398P (1997) 97. Jpn. Appl. 06-09 313; Chem. Abstr. 120 263839 (1994) 98. Jpn. Appl. 08-277 276; Chem. Abstr. 126 47213 (1997) 99. Jpn. Appl. 08-277 277; Chem. Abstr. 126 47214 (1997) 100. BRD Appl. 19 750 012; Ref. Zh. Khim. 09 O 383P (2000) 101. BRD Appl. 19 842 354; Ref. Zh. Khim. 03 O 367P (2001) 102. K Burak, Z Machon Pharmazie 47 492 (1992); Chem. Abstr. 120 298 527 (1994) 103.Pol. P. 167 891; Chem. Abstr. 125 58 496 (1996) 104. BRD Appl. 19 712 409; Ref. Zh. Khim. 20 O 326P (1999) 105. Eur. Appl. 542 468; Chem. Abstr. 119 139 214 (1993) 106. US P. 5 508 417; Chem. Abstr. 125 58 497 (1996) 107. X-P Yang, Z-M Li, L-X Wang, Y-H Li Chem. J. Chin. Univ. 19 228 (1998); Ref. Zh. Khim. 24 O 806 (1998) 108. A Alberola, L Calvo,M T R Rodriguez,M C Sanudo J. Heterocycl. Chem. 30 393 (1993) 109. A Alberola, L Calvo,M T R Rodriguez,M C Sanudo J. Heterocycl. Chem. 32 537 (1995) 110. U Lipnicka, Z Machon Acta Pol. Pharm. 50 235 (1993); Chem. Abstr. 121 35 413 (1994) 111. X-P Yang, Z-M Li, J Lui, H-S Chen Chin. J. Appl. Chem. 16 115 (1999); Ref. Zh. Khim. 22 Zh 351 (1999)Isothiazoles (1,2-thiazoles): synthesis, properties and applications 112.Can. Appl. 2 152 156; Chem. Abstr. 124 317 143 (1996) 113. BRD Appl. 1 975 0011; Ref. Zh. Khim. 11 O 410P (2000) 114. E E Swayze, L B Townsend J. Heterocycl. Chem. 30 1379 (1993) 115. E E Swayze, L B Townsend J. Org. Chem. 60 6309 (1995) 116. C J Shishoo, M B Devani, S Ananthan, V S Bhadti, C V Ullas J. Heterocycl. Chem. 25 759 (1988) 117. S G Zlotin, K S Chunikhin, M O Dekaprilevich Mendeleev Commun. 97 (1997) 118. S G Zlotin, A V Bobrov, K S Chunikhin Izv. Akad. Nauk, Ser. Khim. 1350 (1999) d 119. S G Zlotin, A V Bobrov Izv. Akad. Nauk, Ser. Khim. 957 (2000) d 120. US P. 3 341 547; Chem. Abstr. 68 114596 (1968) 121. Jpn. Appl. 05-59 024; Chem. Abstr. 119 117 242 (1993) 122. US P. 3 155 678; Chem. Abstr. 62 2778 (1965) 123.US P. 5 484 934; Ref. Zh. Khim. 23 O 373P (1997) 124. Eur. Appl. 604 978; Chem. Abstr. 121 134 107 (1994) 125. J G Samaritoni, J M Babcock,M L Schlenz,G W Johnson J. Agr. Food Chem. 47 3381 (1999); Ref. Zh. Khim. 08 O 401 (2000) 126. K Ohkata, Y Ohyama, K Akiba Heterocycles 37 859 (1994); Chem. Abstr. 121 57 558 (1994) 127. M Konrad, F Meyer, M Buechner, K Heinze, L Zsolnai Chem. Ber.-Recl. 130 95 (1997) 128. N V Onyamboko,M Renson, C Paulmier Bull. Soc. Chim. Belg. 96 407 (1987) 129. M S Mohamed Egypt. J. Pharm. Sci. 35 427 (1994); Chem. Abstr. 123 285 924 (1995) 130. A V Bobrov, B B Averkiev, S G Zlotin, M Yu Antipin Izv. Akad. Nauk, Ser. Khim. 1226 (2001) d 131. B Schulze, K Illgen J. Prakt. Chem., Chem.-Ztg. 339 1 (1997); Chem.Abstr. 126 117 919 (1997) 132. J L Marco, S Ingate Tetrahedron Lett. 38 4835 (1997) 133. S T Ingate, J L Marco, M Witvrouw, C Pannecouque, E DeClercq Tetrahedron 53 17795 (1997) 134. J L Marco, S T Ingate, P Manzano Tetrahedron Lett. 39 4123 (1998) 135. J L Marco, S T Ingate, C Jaime, I Bea Tetrahedron 56 2523 (2000) 136. J L Marco, S T Ingate, P M Chinchon Tetrahedron 55 7625 (1999) 137. S G Zlotin, A I Gerasyuto Izv. Akad. Nauk, Ser. Khim. 396 (1999) d 138. Sh Li, Zh Li Guangzhou Huagong 22 10 (1994); Chem. Abstr. 123 313 798 (1995) 139. BRD Appl. 19 652 531; Chem. Abstr. 127 135 791 (1997) 140. R Glinka, E Zak, K Walczynski Zesz. Nauk. Politech. Lodz., Technol. Chem. Spozyw. 708 (53) 51 (1995); Chem. Abstr. 124 86 868 (1996) 141.US P. 5 466 818; Ref. Zh. Khim. 24 O 436P (1997) 142. Sh Li, X Tan Jingxi Huagong (Fine Chem) 16 4 (1999); Ref. Zh. Khim. 22 O 382 (1999) 143. Jpn. Appl. 06-192 245; Chem. Abstr. 121 280 633 (1994) 144. US P. 5 420 290; Ref. Zh. Khim. 10 O 87P (1997) 145. K Hartke, C Ashry Pharmazie 51 638 (1996); Chem. Abstr. 125 300 769 (1996) 146. O Carugo, F Clerici, D Pocar Tetrahedron 49 9117 (1993) 147. F Clerici, F Galletti, D Pocar, P Rowersi Tetrahedron 52 7183 (1996) 148. F Clerici, T Ferrario, M L Gelmi, R Marrelli J. Chem. Soc., Perkin. Trans. 1 2533 (1994) 149. P Baggi, F Clerici, M L Gelmi, S Mottadelli Tetrahedron 51 2455 (1995) 150. S Abou El Maaty,M S Mohamed, F El Telebany Egypt. J. Pharm. Sci. 33 441 (1992); Chem. Abstr.121 57 440 (1994) 151. A Rolfs, J Liebscher Angew. Chem. 105 797 (1993) 152. Eur. Appl. 583 561; Chem. Abstr. 120 244661 (1994) 153. A Rolfs, P G Jones, J Liebscher J. Chem. Soc., Perkin Trans. 1 2339 (1996) 154. S H Kim, K Kim J. Heterocycl. Chem. 30 928 (1993) 155. B Friedrich, A Fuks, B Schulze Zh. Org. Khim. 30 1404 (1994) b 156. B Schulze, K Rosenbaum, J Hilbig, L Weber J. Prakt. Chem.- Chem. Ztg. 334 25 (1992) 157. B Schulze, U Obst, G Zahn, B Friedrich, R Cimirgalia, H-J Hofmann J. Prakt. Chem.-Chem. Ztg. 337 175 (1995) 158. J W Pavlik, P Tongcharoensirikul, N P Bird, A C Day, J A Barltrop J. Am. Chem. Soc. 116 2292 (1994) 159. J W Pavlik, P Tongcharoensirikul J. Org. Chem. 65 3626 (2000) 160. M de Wang, H Alper J. Organomet. Chem.451 169 (1993) 693 161. S H Kim, Y Y Lee, K Kim, J H Kim Bull. Korean Chem. Soc. 15 273 (1994); Chem. Abstr. 121 108 116 (1994) 162. E M Beccalli, F Clerici,M L Gelmi Tetrahedron 55 14975 (1999) 163. D M Argilagos, A Linden, R W Kunz, H Heimgartner Chimia 51 455 (1997); Ref. Zh. Khim. 13 Zh 264 (1998) 164. D M Argilagos,M J Trimino, A M Cabrera, A Linden, H Heimgartner Helv. Chim. Acta 80 273 (1997); Ref. Zh. Khim. 3 Zh 290 (1999) 165. D M Argilagos, R W Kunz, A Linden, H Heimgartner Helv. Chim. Acta 81 2388 (1998); Ref. Zh. Khim. 14 Zh 129 (1999) 166. B Unterhalt, C Langfermann,M Majdrpour, S Kirrbach, A Kolberg, B Schulze Pharmazie 53 764 (1998); Ref. Zh. Khim. 9 Zh 264 (1999) 167. B Schulze, A Noack, A Kolberg, in 6-ya Mezhdunarodnaya Konferentsiya `Khimiya Karbenov i Rodstvennykh Intermediatov' (Programma i Tez.Dokl.), S Peterburg, 1998 [The 6th International Conference `Chemistry of Carbenes and Related Intermediates' (Programme and Abstracts of Reports), S Petersburg, 1998] p. 137 168. F Clerici, E Erba, M L Gelmi,M Valle Tetrahedron 53 15 859 (1997) 169. F Clerici, M L Gelmi, R Soave, M Valle Tetrahedron 54 11 285 (1998) 170. E Coutouli-Argiropoulou, C Anastasopoulos J. Heterocycl. Chem. 33 731 (1996) 171. E M Beccalli, F Clerici,M L Gelmi Tetrahedron 55 2001 (1999) 172. N N Mel'nikov Zh. Vses. Khim. O-va im D I Mendeleeva 33 602 (1988) 173. BRD Appl. 19 614 858; Ref. Zh. Khim. 19 O 386P (1998) 174. Eur. Appl. 761 654; Chem. Abstr. 126 277 469 (1997) 175.US P. 5 438 033; Chem. Abstr. 123 1221 (1995) 176. BRD Appl. 19 620 135; Ref. Zh. Khim. 4 O 467P (1999) 177. US P. 5 324 837; Chem. Abstr. 121 205 339 (1994) 178. US P. 5 338 856; Chem. Abstr. 121 300 887 (1994) 179. US P. 6 096 898; Ref. Zh. Khim. 11 O 334P (2001) 180. Eur. Appl. 578 246; Chem. Abstr. 120 323 562 (1994) 181. WO PCT 93 19 054; Chem. Abstr. 120 107 030 (1994) 182. Eur. Appl. 538 231; Chem. Abstr. 119 160 256 (1993) 183. WO PCT 93 13 078; Chem. Abstr. 119 271 189 (1993) 184. Eur. Appl. 648 757; Chem. Abstr. 123 55 869 (1995) 185. Zh-M Li, H-S Chen, J Liu, Sh-Ih Lish Chem. J. Chin. Univ. 20 395 (1999); Ref. Zh. Khim. 20 Zh 277 (1999) 186. Br. Appl. 2 274 779; Chem. Abstr. 121 295 087 (1994) 187. Br. Appl. 2 304 574; Ref.Zh. Khim. 23 O 378P (1997) 188. US P. 5 668 083; Ref. Zh. Khim. 11 O 458P (1999) 189. Jpn. Appl. 06-227 912; Chem. Abstr. 121 295 094 (1994) 190. Can. Appl. 2 058 252; Chem. Abstr. 118 141 816 (1993) 191. Can. Appl. 2 069 453; Chem. Abstr. 121 29 268 (1994) 192. US P. 5 430 046; Ref. Zh. Khim. 2 O 287P (1997) 193. Jpn. Appl. 08-67 853; Chem. Abstr. 125 36 071 (1996) 194. WO PCT 9614092; Chem. Abstr. 125 95 454 (1996) 195. BRD Appl. 4 344 549; Ref. Zh. Khim. 21 O 398P (1997) 196. RF Appl. 96 122 055; Ref. Zh. Khim. 19 O 388P (2000) 197. US P. 5 595 575; Ref. Zh. Khim. 13 N 162P (1998) 198. Eur. Appl. 712 039; Chem. Abstr. 125 99 942 (1996) 199. Jpn. Appl. 04-194 928; Chem. Abstr. 118 90 712 (1993) 200. Jpn. Appl. 04-152 340; Chem.Abstr. 118 90 693 (1993) 201. Jpn. Appl. 06-03 780; Chem. Abstr. 121 22 412 (1994) 202. Jpn. Appl. 05-333 486; Chem. Abstr. 121 22 406 (1994) 203. Eur. Appl. 508 457; Chem. Abstr. 118 157 782 (1993) 204. Jpn. Appl. 04-177 239; Chem. Abstr. 118 70 018 (1993) 205. Jpn. Appl. 04-128 839; Chem. Abstr. 118 112 860 (1993) 206. Eur. Appl. 529 794; Chem. Abstr. 119 259 396 (1993) 207. Eur. Appl. 549 175; Chem. Abstr. 119 237 893 (1993) 208. Jpn. Appl. 04-260 036; Chem. Abstr. 118 136 118 (1993) 209. US P. 5 514 505; Chem. Abstr. 125 127 644 (1996) 210. Jpn. Appl. 08-201 979; Chem. Abstr. 125 288 680 (1996) 211. Jpn. Appl. 05-331 379; Chem. Abstr. 121 95 875 (1994) 212. Jpn. Appl. 09-133 977; Chem. Abstr. 127 57 952 (1997) 213. R Matissek GJT-Suppl.(7) 5; 8 (1987); Chem. Abstr. 108 137 671 (1988) 214. Czech. P. 276 924; Chem. Abstr. 121 163 678 (1994) 215. Dtsch. Lebensm.-Rundsch. 89 181 (1993); Chem. Abstr. 121 163 671 (1994) 216. Eur. Appl. 534 296; Chem. Abstr. 119 162 371 (1993)694 217. Eur. Appl. 545 420; Chem. Abstr. 119 162 375 (1993) 218. Jpn. Appl. 09-292 684; Chem. Abstr. 128 68 443 (1998) 219. Jpn. Appl. 07-207 090; Chem. Abstr. 123 230 303 (1995) 220. WO PCT 9 612 407; Chem. Abstr. 125 28 275 (1996) 221. US P. 5 591 759; Ref. Zh. Khim. 5 O 404P (1998) 222. US P. 5 523 020; Ref. Zh. Khim. 10 O 92P (1998) 223. Eur. Appl. 594 440; Chem. Abstr. 121 258 107 (1994) 224. US P. 5 552 423; Ref. Zh. Khim. 9 O 436P (1999) 225. Jpn. Appl. 08-198 714; Chem. Abstr. 125 240 850 (1996) 226.Jpn. Appl. 08-38 195; Chem. Abstr. 124 311 832 (1996) 227. Jpn. Appl. 08-38 196; Chem. Abstr. 124 311 833 (1996) 228. US P. 5 908 931; Ref. Zh. Khim. 07 O 47P (2000) 229. Jpn. Appl. 07-196 403; Chem. Abstr. 123 342 819 (1995) 230. Jpn. Appl. 06-40 812; Chem. Abstr. 121 29 270 (1994) 231. Eur. Appl. 706 974; Chem. Abstr. 124 324 873 (1996) 232. Jpn. Appl. 08-20 676; Chem. Abstr. 124 319 797 (1996) 233. US P. 5 670 055; Chem. Abstr. 127 298 502 (1997) 234. W W Bingaman, G L Willingham Int. Biodeter. Biodegr. 34 387 (1994); Chem. Abstr. 124 79 433 (1996) 235. US P. 6 010 693; Ref. Zh. Khim. 1 O 377P (2001) 236. BRD Appl. 19 654 147; Ref. Zh. Khim. 13 O 436P (1999) 237. Eur. Appl. 542 489; Chem. Abstr. 119 111 272 (1993) 238. Jpn. Appl. 05-163 107; Chem. Abstr. 119 175 864 (1993) 239. Jpn. Appl. 05-170 608; Chem. Abstr. 119 175 869 (1993) 240. Jpn. Appl. 05-286 815; Chem. Abstr. 120 127 766 (1994) 241. US P. 5 288 693; Chem. Abstr. 121 35 595 (1994) 242. Jpn. Appl. 06-87 705; Chem. Abstr. 121 76 166 (1994) 243. Jpn. Appl. 06-148 957; Chem. Abstr. 121 241 882 (1994) 244. Jpn. Appl. 06-227 916; Chem. Abstr. 121 295 095 (1994) 245. Jpn. Appl. 07-258 009; Chem. Abstr. 124 23 925 (1996) 246. Eur. Appl. 686 346; Chem. Abstr. 124 79 443 (1996) 247. Eur. Appl. 686 347; Chem. Abstr. 124 79 444 (1996) 248. W Anker Microb. Materialzerstoerung Materialschutz 151 (1995); Chem. Abstr. 124 236 544 (1996) 249. US P. 5 494 588; Chem. Abstr. 124 241 661 (1996) 250. Jpn. Appl. 08-165 206; Chem. Abstr. 125 161 120 (1996) 251. Jpn. Appl. 07-330 520; Chem. Abstr. 124 223 707 (1996) 252. Jpn. Appl. 07-277 910; Chem. Abstr. 124 48 313 (1996) 253. Jpn. Appl. 07-277 911; Chem. Abstr. 124 48 314 (1996) 254. Jpn. Appl. 08-239 694; Chem. Abstr. 126 3076 (1997) 255. US P. 5 670 529; Chem. Abstr. 127 283 428 (1997) 256. Jpn. Appl. 09-209 272; Chem. Abstr. 127 221 913 (1997) 257. Eur. Appl. 834 253; Chem. Abstr. 128 254 064 (1998) 258. Jpn. Appl. 10-27 381; Chem. Abstr. 128 174 208 (1998) 259. Eur. Appl. 827 939; Chem. Abstr. 128 196 442 (1998) 260. US P. 5 703 105; Chem. Abstr. 128 106 408 (1998) 261. Pol. P. 169 519; Ref. Zh. Khim. 17 O 376P (1997) 262. Eur. Appl. 774 444; Chem. Abstr. 127 55 587 (1997) 263. Jpn. Appl. 09-263 504; Chem. Abstr. 127 342 912 (1997) 264. BRD Appl. 19 651 351; Ref. Zh. Khim. 16 O 440P (1999) 265. BRD Appl. 19 734 244; Ref. Zh. Khim. 07 O 138P (2000) 266. Jpn. Appl. 04-290 806; Chem. Abstr. 118 118 948 (1993) 267. Jpn. Appl. 08-193 014; Chem. Abstr. 125 240 846 (1996) 268. Jpn. Appl. 09-151 101; Chem. Abstr. 127 132 269 (1997) 269. Jpn. Appl. 08-183 703; Chem. Abstr. 125 188 330 (1996) 270. Jpn. Appl. 08-183 704; Chem. Abstr. 125 188 331 (1996) 271. Jpn. Appl. 08-253 404; Chem. Abstr. 126 28 030 (1997) 272. J J Sheets, A Schmidt, J G Samaritoni, J M Gifford J. Agr. Food Chem. 45 4826 (1997) 273. BRD Appl. 19 542 372; Chem. Abstr. 127 50 631 (1997) 274. Jpn. Appl. 08-23 136 ; Chem. Abstr. 126 3075 (1997) 275. Jpn. Appl. 08-245 561; Chem. Abstr. 126 31 346 (1997) 276. US P. 5 952 359; Ref. Zh. Khim. 09 O 384P (2001) 277. R Hara, E Nakai, H Hisamichi, N Nagano J. Antibiot. 47 477 (1994) 278. US P. 5 338 857; Chem. Abstr. 123 83 354 (1995) 279. Eur. Appl. 578 477; Chem. Abstr. 120 261 340 (1994) 280. WO PCT 9 500 501; Chem. Abstr. 124 55 954 (1996) 281. Eur. Appl. 587 378; Chem. Abstr. 120 290 112 (1994) 282. M J Ashton, D C Cook, G Fenton, J-A Karlsson, M N Palfreyman, D Raeburn, A J Ratcliffe, J E Souness, S Thurairatham, N Vicer J. Med. Chem. 37 1696 (1994) 283. WO PCT 9 815 530; Chem. Abstr. 128 294 695 (1998) 284. Eur. Appl. 0 994 107; Ref. Zh. Khim. 19 O 117P (2000) R V Kaberdin, V I Potkin 285. U Lipnicka, Z Machon Acta Pol. Pharm. 54 207 (1997); Chem. Abstr. 127 346 328 (1997) 286. Jpn. Appl. 07-324 007; Chem. Abstr. 124 253 329 (1996) 287. R Devos, Y Guisez, G Plaetinck, S Cornelis, J Tavernier, J van der Heyden, L H Foley, J E Scheffler Eur. J. Biochem. 225 635 (1994) 288. WO PCT 94 14801; Chem. Abstr. 121 179 617 (1994) 289. O N Zefirova, N S Zefirov Usp. Khim. 70 382 (2001) [Russ. Chem. Rev. 70 333 (2001)] 290. I T Forbes, P Ham, D H Booth, R T Martin,M Thompson, G S Baxter, T P Blackburn, A Glen, G A Kennet,M D Wood J. Med. Chem. 38 2524 (1995) 291. I T Forbes, G E Jones, O E Murphy, V Holland, G S Baxter J. Med. Chem. 38 855 (1995) 292. O N Zefirova, N S Zefirov Zh. Org. Khim. 36 1273 (2000) b 293. L Matzen, B Ebert, T B Stensbol, B Frolund, J W Jaroszewski, P Krogsgaard-Larsen Bioorg. Med. Chem. 5 1569 (1997) a�Dokl. Chem. (Engl. Transl.) b�Russ. J. Org. Chem. (Engl. Transl.) c�Chem. Heterocycl. Compd. (Engl. Transl.) d�Russ. Chem. Bull., Int. Ed. (Engl.