1,2-Benzisothiazoles, synthesis

Benzisothiazoles.—Synthesis. A number of 1,2-benzisothiazole-3-acetic acids (128) have been prepared with the aim of studying their potential activity as plant hormones. They were produced, usually in near-quantitative yields, by the action of hydroxylamine on substituted 4-hydroxy-l-thiocoumarins (127) (c/. ref. 56). 5-Chloro-l,2-benzisothiazole-3-acetic acid proved very potent, possessing an activity about three times that of of heteroauxin. ... 

Benzisothiazoles.—Synthesis, A novel route to 2,1-benzisothiazoles by the thermal decomposition of 2-azidoaryl thioketones has been briefly reported. It proceeds by loss of nitrogen due to a nucleophilic attack of the thiono-group on the azide function. Another simple one-step synthesis, involving an oxidation-reduction process, is the action of tbionyl chloride on o-toluidine. The reaction is carried out in boiling p-xylene and affords the heterocycle in 30% yield. ... 

The succinimide derivative (234) can be used in peptide synthesis for conversion of amino acids into their succinimide esters (235 Scheme 41) (79CL1265). 3-Substituted mercapto-1,2-benzisothiazole 1,1-dioxides (236) have been recommended as an odourless means of storage of thiols. The latter are readily regenerated by the action of piperidine (81CL1457). 

Benzisothiazole, 4-chloro-nitration, 6, 154 nucleophilic reactions, 6, 154 synthesis, 6, 169... 

Benzisothiazole-3-acetic acid decarboxylation, 6, 149 reduction, 6, 155 synthesis, 6, 170... 

Thieno[3,4-d ]isothiazole-4-carboxylic acid synthesis, 6, 1023 Thienoisothiazoles benzisothiazoles from, 6, 172 Thieno[3,4-c]isothiazoles reactions, 6, 1034 synthesis, 6, 1043... 

There are two series of benzisothiazoles, derived from benz[c]iso-thiazole (2) and benz[d]isothiazole (3), and both, if the benzene ring were suitable weakened, could doubtless be oxidized to isothiazole-dicarboxylic acids. In their first synthesis Adams and Slack... 

Two new pyridone derivatives (14) and (15) have been prepared by cycloaddition of saccharin pseudochloride (16 R = Cl) with Danishefsky s diene and by treatment of (16 R = Me) with ciimamoyl chloride. The synthesis of two more ting expanded derivatives (17) and (18) via cycloaddition to benzisothiazoles was also described <96T3339>. 

Bassin et al. reported a convenient synthesis of 3-methylsulphonamido-l,2-benzisothiazole-1,1 -dioxide 15 from 14 via initial condensation with ammonia followed by an internal Michael reaction <00JHC181>. 

The first synthesis of ziprasidone was disclosed by Lowe and Nagel in a patent issued to Pfizer in 1989. Initially, the left-hand fragment of ziprasidone, 3-benzisothiazolylpiperazine (40), was prepared according to the method of Yevich and coworkers (Scheme 12). The amide 38 was treated with phosphorous oxychloride to give 3-chloro-l,2-benzisothiazole (39). Compound 39 was then reacted with molten piperazine at 125 °C to provide piperazine 40 in 68% yield. 

Pfizer has also prepared both and " C-labelled ziprasidone (Schemes 18 and 19) to detennine its metabolism and tissue distnbution. It was envisioned that tritium could be introduced in the last step of e synthesis utilizing the selective replacement of a bromine atom on the benzisothiazole nng. Therefore, the synthesis began with the bromination of 39 using bromine in acetic acid with FeCls catalysis. The dibrominated regioisomer 60 was isolated by liquid chromatography in 18% yield and reacted with... 

The largest proportion of the dyes of this type, which can range from yellow to blue in colour, is of the homocyclic type. Examples such as those derived from 5-amino-l,2,4-thiadiazoles (32), 2-aminobenzothiazoles and 3-amino-2,l-benzisothiazoles (74MI11201) are in the minority. Synthesis is usually via diazotization of the appropriate heteroaromatic amino group and coupling with quaternary aniline derivatives. 

Recent Advances in the Chemistry of Benzisothiazoles and Other Polycyclic Isothiazoles, 38, 105 Sulfur Transfer Reagents in Heterocyclic Synthesis, 30, 47. 

An unusual synthesis reported recently13 is the reaction of 3-acetamido-2-nitrobenzothiophene (17) with ferrous oxalate. The major products are 3-cyano-l,2-benzisothiazole (18) and the corresponding amide (19). Once again the mechanism of this curious... 

Although any of the foregoing methods could, in principle, have been applied to the synthesis of substituted 2,1-benzisothiazoles, no such attempt was made and until 1963 the parent compound (2) was the sole representative of this heterocyclic system. In that year a group from the Parke, Davis Company filed a patent application100 in which the preparation of a number of 3-substituted 2,1-benzisothiazoles was described. This application, shortly followed by a definitive paper,101 indicated how o-aminothiobenzamides (69) could be oxidized, and o-nitrothiobenzamides (70) reduced, with concomitant ring closure to yield 3-amino-2,l-benzisothiazoles (71). 

Temple DL, Jr. Synthesis and biological evaluation of l-(l,2-benzisothiazol-3-yl)-and (l,2-benzisoxazol-3-yl)piperazine derivatives as potential antipsychotic agents./. Med. Chem., 1986, 29, 359—3 69. 

II. Synthesis and antipsychotic activity of l-[4-[[4-( 1,2-benzisothiazol-3-yl) -1-piperazinyl]butyl]-l,2-cis-cyclohexanedi-carboxamide (SM-9018) and related... 

The data on the synthesis of nitrated 2,1-benzisothiazoles are rather scarce in comparison with the corresponding benzisoxazoles. It has been reported that, like other 2-aminotoluenes, 2-amino-4-nitrotoluene reacts with thionyle chloride in xylene to form 6-nitro-2,l-benzisothiazole, whereas 2-amino-5-nitrotoluene does not enter into this reaction (Scheme 2.93) [543],... 

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