Isothiazole Derivatives

These cycloadditions have been applied also to naphthoquinones (50G140 68G891 69G565) to give derivatives of 194 and 195. Derivatives of 194 

Quinones undergo 1,3-dipolar cycloaddition also with arylhydroxamoyl chlorides to give 194 (68BCJ2206). Another system, 196, was obtained from 2-acetyl-3-amino- or -anilinoquinones and hydroxylamine or from 2-car-balkoxy-3-chloroquinones and sodium azide or primary and secondary aliphatic amines (67TL4313 71AG442 74S30 76IJC(B)575). 

Another variant is oxidative cyclization of 3-amino-2-carbalkoxyquinones with lead tetraacetate (85JHC697). Compounds of the 196 system can be regarded as intramolecular stabilized nitrenes. They react readily with dimethyl sufoxide by ring opening of the heterocyclic part (85JHC701), but derivatives of 198 were also obtained as by-products (85JHC705). 

From thermolysis of ethyl azidoformate with 1,4-naphthoquinone, a mixture of compounds was obtained, among them a product with the probable structure 197 (77CJC2363). 

So far, there are only few representatives of the isothiazolo-4,5-dione system 199, and they were obtained from nitric acid oxidation of the hydroxy precursors (27LA264). 

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The stability of isothiazole derives from the fact that it has an aromatic delocalized ir-electron system. The NMR chemical shifts, which depend, inter alia, on ring currents, and the high stability of the molecular ions in mass spectrometry, are typical of aromatic compounds, and X-ray measurements confirm the partial double bond character of all the bonds of the ring. 

The isothiazole ring does not occur in nature. By far the most important synthetic isothiazole derivative is saccharin. This was the first non-carbohydrate sweetening agent to be discovered, as long ago as 1879. It is about 300 times as sweet as sucrose, and is still used in many countries as a non-nutritive sweetener. After it was found that administration of massive doses to rats caused bladder cancer, its use was banned in the New World, but the controversy continues as to whether there is any danger when it is used in small quantity. Saccharin is also used as an additive in electroplating processes (73AHC(15)233). 

Semiempirical calculations on 4-methylisothiazole showed that the reaction can occur through an ICI mechanism with the formation of the Dewar isothiazole derivative (Fig. 18) (OOOUPl). In fact, the triplet state of the isothiazole cannot evolve to the biradical. The ZI mechanism can be excluded Only the intermediate 96 showed an acceptable energy however, it is a resonance stmeture of Dewar isothiazole. 

Calculations allow one to justify the observed behavior (Fig. 19) (99MI233). In the case of 3- and 5-phenylisothiazole, the reaction should implicate a Dewar isomer, because the excited triplet isothiazole derivative cannot be converted into the corresponding biradical. 

The addition of trithiazyl trichloride (NSC1)3 to 2,5-disubstituted furans and to N-2,5-trisubstituted pyrroles has led to the formation of isothiazole derivatives <96JHC1419>. 

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. 

Synthesis of another triazole derivative was described by Clerica et al. [53]. This synthetic strategy involved reaction of an isothiazole derivative (e.g., compound 48) with an equimolecular quantity of NaN3 in a variety of solvents, e.g., different alcohols, THF, etc. Acetonitrile was used to produce compound 49 in a 30% yield, Scheme 8. 

The reduction of some thiazole and isothiazole derivatives was discussed in Part I. 

Isothiazoles have also been incorporated into a wide range of established drugs including phenothiazines,123 sulfones,121 sulfonamides,3,66,156 thiosemicarbazones,140,157 amidines,158 nitrohetero-cycles,159 and benzimidazoles,160 but this approach does not appear to have resulted in any major improvements. However, many isothiazoles not directly related to known drugs have biological activity, and representatives are listed in Table I, No attempt has been made to include the numerous patents which mention isothiazole derivatives as part of a series, but for which no special claims are made. 

Treatment of the l//-pyrazolo[4,3-with dimethyl sulfate yielded the corresponding salt (35) in good yield (85KGS223). 

The spectra of 16 isothiazole derivatives including 4-nitroisothiazoles have been examined [1324], Electron impact induces cleavage of the S-N bond and abstraction of a fragment of type R3CN or HCN occurs [1324],... 

Finally, 116 pesticides (including several isothiazole derivatives) were computationally evaluated in order to derive a QSAR model for avian oral toxicity <2006MI616>. 

Different techniques have been used to determine the molecular geometry of isothiazole derivatives and saccharin salts, such as neutron diffraction, gas-phase electronic diffraction, and microwave spectroscopy, and these were reported in CHEC(1984) and CHEC-II(1996) <1984CHEC(6)131, 1996CHEC-II(3)319>. 

Mass spectrometry (MS) and tandem mass spectrometry (MS/MS) play an important role in the identification of unknown compounds. Different ionization techniques have been used in studying isothiazole derivatives, such as electronic ionization (El), desorption chemical ionization (DCI), fast atom bombardment (FAB), field desorption (FD), and chemical ionization (Cl). Different MS/MS experiments have been described, such as investigation of metastable and collision-induced dissociations to study isothiazoles gas-phase ion chemistry. In addition, MS and MS/MS have been used to differentiate isothiazole isomers differing in the position of endocyclic groups or exocyclic substituents <1998THS(2)471, 1999THS(3)369, 2000THS(4)405>. 

Chiroptical properties of isothiazole derivatives have been studied using circular dicroism (CD). Optically active sulfinamide R- +)-49a. (R=l-Ad) shows a positive first Cotton effect at 284nm while A (- -)-49b (R = 2,4,6-Me3C6H2) has a negative one at 277 nm <2005JOC868>. 

General features of the conformations of isothiazole derivatives were discussed in CHEC-II(1996) <1996CHEC-11(3)319>. Isothiazole and the benzisothiazoles are planar molecules, as are the corresponding A,A-dioxides, saccharin, thiosaccharin, and their salts. 1,2-Benzisothiazoline A,A-dioxide in the crystalline state exists as a 1 1 mixture of two conformers. 

A great contribution to understanding the stereochemistry and conformations of isothiazole derivatives has come from the use of the X-ray technique (see Section 4.05.3.1.1) and NMR analyses (see Section 4.05.3.2.1). A vast amount of literature concerning QSAR studies and theoretical calculations about conformations has been published in the last decade (see Section 4.05.2.1). 

Few examples of functionalization on the benzene ring of benzisothiazole have been reported (see Section 4.05.7.2). Studies on the reactivity of unsaturated chains in cycloaddition reactions have been reported (see Section 4.05.7.3). The high reactivity of 4-vinylisothiazolin-3-one A-oxides in Diels-Alder cycloadditions, both as diene and dienophile, is illustrated by their tendency to dimerize. 5-Vinylisothiazole A,A-dioxides react at the vinyl function with different 1,3-dipoles. Isothiazolo-3-sulfolenes 265 give an o-quinodimethane which can be trapped with a dienophile. Different isothiazole derivatives substituted with a carbon chain functionalized with heteroatoms have been prepared as ligands for the formation of complexes. 3-Oxocamphorsulfonimide reacts with the anion of alkynes and several studies on the reactivity of the products with electrophiles are reported. 

Several dihydro- or tetrahydro-isothiazole derivatives are used mainly as chiral scaffolds in diastereoselective syntheses. Among these, Oppolzer s sultam 582 (R = H) has been the most frequently used when functionalized at nitrogen with different acyl residues. A method for the removal of this chiral auxiliary has been described <1998SL882>. 

Isothiazole derivatives manifest a broad spectrum of useful properties and have applications in several fields. Several examples were reported in CHEC(1984) <1984CHEC(6)131>, CHEC-II(1996) <1996CHEC-II(3)319>, and other reviews <2002RCR673, 2002AHC(83)71, 2002SR279, 2002SR79, 2007THC(9)179>. 

Some interesting developments concerning the synthesis and the reactivity of isothiazole derivatives were reported in 2007. 

Isoxazole and Isothiazole Derivatives. Bioisosteric replacement of the pyridine ring in nicotine generated a series of novel isoxazole compounds that are selective and potent neuronal nAChR agonists, as exemplified by ABT-418 (71) (Table 14.8) (299). Among the variety of substituents examined at C3 cf the isoxazole, methyl turns out to be optimal, even though other substituents, such as C2-C4 linear alkyl, CF Br, and benzyl (not phenyl), still provide potent analogs. The 3-des-methyl... 

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