Synthesis of isothiazoles

A novel synthesis of alkylsulfanylisothiazoles 230 starts with sodium a-cyanoketene dithiolates 227, obtained by the reaction of cyanoacetamides 226 with carbon disulfide in the presence of sodium ethoxide 06SC825 . Treatment of 227 with sulphur and piperidine acetate generates sodium isothiazole-3,5-dithiolates 229. The formation of 229 is assumed to arise from the addition of anionic sulphur to the nitrile group in 227 to give the intermediate 228, which cyclizes upon elimination of anionic sulphur to yield 229. Salts 229 are readily alkylated to furnish 3,5-bis(alkylthio)isothiazole derivatives 230. 

A novel synthesis of isothiazolidines involves sulfonium ylides, formed by the reaction of thietanes and nitrenes 06TL1109 . Exposure of A-(/ -tolylsulfonyl)imino)phenyliodinane 232 with excess of thietanes 231 (5 equiv) in the presence of a catalytic amount of Cu(II) 

A series of benzisothiazolone derivatives 238 has been prepared from methylthiosalicylate 235 O60L4811 . The key cyclization step features the formation of a TV-acylnitrenium ion 237, generated by the hypervalent iodine reagent, phenyliodine(III)bis(trifluoroacetate) (PIFA). This ion cyclizes to benzisothiazol-3-one 238 upon intramolecular trapping of the thiol moiety. 

Radical cyclization of acyclic sulfinamides 239 provides easy access to cyclic sulfinamides 241 06AG(E)633 . Conceivably, the reaction pathway involves thiophilic attack by the aryl radical with a concomitant or successive expulsion of the p-tolyl or tert-butyl radical. 

A practical synthesis of the bicyclic dienyl sultam 246 has been reported 06JOC6573 . The key step of the ring-closing metathesis (RCM) represented by conversion of 243 to 244 has to be implemented prior to the sultam formation (244 to 245). Bicyclic sultam is converted to dienyl sultam 246 in two steps. 

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Numerous examples of N—S bond formation using oxidative conditions have been described in the literature. A convenient synthesis of isothiazoles involves the direct oxidation of -y-iminothiols and numerous variations have been studied (see Chapter 4.17), The oxidation of the amidine (248) to give the 3-aminoisothiazole (249) illustrates the reaction scheme (65AHC(4)107, 72AHC(14)1), which has been extended to the synthetically useful 5-amino-4-cyano-3-methylisothiazole (251) obtained by oxidation of (250) with hydrogen peroxide (75JHC883). 

One of the best methods of synthesis of isothiazoles is by direct oxidation of y- iminothiols (169) or their tautomers. The reaction is capable of many ramifications and is represented by the general equation shown in Scheme 27. The substituents represent a wide range of groups. Thus, iminothioamides (169 R = NH2) are oxidized to give 3-alkyl-5-aminoisothiazoles (170 = NH2), amidines (169 R = NH2) produce 3-amino compounds,... 

If ammonium thiocyanate is used, the ammonium ion can itself provide a nitrogen atom for heterocyclic ring construction. Such nitrogen and sulfur transfer is the basis of an elegant synthesis of isothiazoles (15) from 3-chloropropenals (16).18... 

Sulfur dioxide has long been used in an industrial synthesis of isothiazole from propene, sulfur dioxide, and ammonia over a catalyst at 200°C.51... 

This analysis suggests that condensation of 4.10 with hydroxylamine 4.11, hydrazine 4.12, or thiohydroxylamine 4.13 should give the corresponding 1,2-azole..This approach represents an important route to isoxazoles and pyrazoles, but thiohydroxylamine 4.13, although known, is far too unstable for synthetic purposes. The synthesis of isothiazoles will be mentioned later. The mechanism of the forward process is illustrated by the preparation of isoxazole 4.14 and is simply two consecutive condensations. 

The synthesis of isothiazole-fused sulfone 265 is based on the same approach and was obtained from sulfolene 520 (see Section 4.05.7.3) <1996TL4189>. Treatment of different heterocyclic n-azidocarbaldehydes with hexamethyl-disilathiane (HMDST) in the presence of HCl as catalyst offers a novel and practicable route to fused isothiazoles 521-523 <1997PS(120)165, 2005SL1965, 2000EJ02171>. 

Sdieme 41 Synthesis of isothiazol-and dihydro-isothiazol-3-one S,S-dioxides Method I... 

A variety of strategies have been developed for the synthesis of the isothiazole ring system, and the route selected will depend on the substituents required and the availability of starting materials. The most useful and general method remains the formation of the S—N bond by oxidative cycli-zation of a suitable S—C—C—C—N unit because such compounds are readily available. Depending on the choice of starting material the route is applicable to the synthesis of isothiazoles, isothiazolin-... 

Nitrile sulfides are well suited for the synthesis of isothiazoles incorporating the C=N-S unit via their 1,3-dipolar cycloaddition reactions with double or triple-bonded dipolarophiles. Benzonitrile sulfide 210 is readily prepared from decarboxylation of oxathiazolone 209 using microwave irradiation <05SC807>. Subsequent cycloadditions to dimethyl acetylene-dicarboxylate (DMAD) and dimethyl fumarate afford 211 and 212, respectively. In the case of ethyl propiolate, a 1 1 regioisomeric mixture of phenylisothiazoles 213 and 214 is obtained. 

The synthesis of isothiazoles involving hexamethyldisilathiane-based thionation has been reviewed <05SL1965>. 

Synthesis of Isothiazoles from -Benzoylpropionamides and Thionyl Chloride (Type A). iV-Phenyl-j3-benzoylpropionamide (2) and SOCI2 give 5-benzoyl-2-phenylisothiazolin-3-one (3). ... 

Synthesis of Isothiazoles from l,3,2-Oxathiazol-5-ones (Type B S-N—C + C-C). The thermal reaction of meso-ionic l,3,2-oxathiazol-5-one [4 R =2,3,4-(MeO)3CeH2] with dimethyl acetylenedicarboxylate (DMAD) at 80 C with CO2 evolution gives 80% of isothiazole (5 R the same) (Scheme 1). ... 

Synthesis of Isothiazoles from Aqueous Ammonia and Thioamide Vinylogues (Type H). Aqueous ammonia transaminates the thioamide vinylogues. In addition, the 3-amino-l-arylpropenethiones, in the presence of elemental sulphur, undergo ring-closure to give 65-95% of 5-arylisothiazoles (9) (Scheme 2). 

Synthesis of Isothiazoles, Isothiazolines, and Isothiazolidines 151 From amidoketones and hydrogen sulphide (Type A C-C-C-N + S) 151 From iminonitriles and mercaptoacetic acid derivatives (Type B C-C-N + S-C) 151 From cyclisation of enaminothiones (Type C N-C-C-C-S) 152 From sulphonamidoacetates and diethyl oxalate (N-S-C + C-C) 152 From ketenes and sulphur di-imides (N-S-C + C-C) 152 Physical Properties of Isothiazoles and Isothiazolines 152 Chemical Properties of Isothiazoles, Isothiazolines, and Isothiazolidines 153... 

The single example of this class that is known so far (555) has been synthesized as a stable precursor for the thermolytic in situ production of the allonoylnitrile A -sulfide 556 the latter is the reactive species in the synthesis of isothiazole (Section XI Scheme 149) and 1,2,4-thiadiazole C-nucleosides (Section XIX Scheme 203). The 5-(tri-0-benzoyl-/3-D-ribofuranosyl)-l,3,4-oxathiazol-2-one (780) was obtained from the 2,5-anhydro-D-allonic acid amide 779 by heating with chlorocarbonylsulfenyl chloride (84JOC2165 91MI21) (Scheme 213). 

Synthesis.—From 1,2-Dithiolans (Type C). The general synthesis of isothiazoles from 1,2-dithiolans (see Organic Compounds of Sulphur, Selenium, and Tellurium, volumes 2, 3, 4, and 5 ) continues to be exploited. The 1,2-dithiolyIium-4-olates (1) are cleaved by ammonia and subsequently cyclize to give isothiazol-4-ols (2 X = OH). Methylation in HCIO4 gives (3), which are convertible into (4) by base. ... 

Isothiazoles, Isoselenazoles, and Isotellurazoles Synthesis.—Several new methods for the synthesis of isothiazoles and benziso-thiazoles have been reported. Nitrile sulphides are probable intermediates in one such synthesis they are produced by the thermolysis of l,3,4-oxathiazol-2-ones... 

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