2.1- Benzisothiazole-3-thiones

Benzisothiazole and its derivatives readily form quaternary salts on treatment with alkyl or benzyl halides. These salts (86) are useful synthetic intermediates the reactions they undergo are summarized in Scheme 2. The products include 2,1-benzisothiazolines,96 quinolones,122,123 benzodiazepi-nones (including a one-step synthesis of the tranquilizer Valium),96 124 o-aminobenzaldehydes and o-aminoaryl ketones,122,125 2,1-benzisothiazole-3-thiones,122 and cyanine dyes,126 the latter resulting from the activation of the methyl group in the 3-position of the quaternary salt (86, R = R = Me). 

N-substituted aminotrifluoromethylbenzenes (36 R=H,Me,Ph) react with Na2S on heating and acidification at >°C to give 2,1-benzisothiazol-3-thiones (37) and small amounts of (38) Acidification at higher temperatures (for R=H) resulted in (38) alone. Thermal conversion of (37) to (38) was observed. The intermediacy of an enamino dithiocarboxylate salt (39) was proposed. This is further substantiated by formation of (40) on addition of CS to (39 R=H) [ in situl. ... 

Thiol-thione tautomers have not been extensively studied, but UV and IR evidence show that 5-phenylisothiazole-3-thiol exists in the SH form. Ring-chain tautomerism of 2,3-dihydro derivatives of 1,2-benzisothiazole can occur (26a 26b) and the position of equilibrium depends very much on the solvent, physical state and nature of the substituents (69JOC919, 81KGS1209). 

Tables II-XI list 1,2-benzisothiazoles, Tables XII-XV 2,1-benzisothiazoles. There are a number of minor groups in these series which, because they appear in only a small number of references, are comparatively easy for the reader to locate, and so they are not tabulated here. These are 2-arylsulfonyl-64 and 2-arylideneamino-1,2-benzisothiazoles58 [(101) and (102), respectively], certain 2,1-benzisothiazole quaternary azo dyes (103),117 2,1-benzisothiazolin-3-ones (97)123 and -3-thiones (95),123,124 3,3 -bis-2,l-benzisothiazol-ylidenes (96),123 and 4,5,6,7-tetrahydro derivatives of types 93,122 99,12s. 27 and 100.125-127...

With the intention of comparing the biological activity of numerous 2-substituted l,2-benzisothiazol-3(277)-ones 88b and their sulfur analogues 88a <1985AHC105, 1994EJM743>, with that of the pyridine series and their derivatives, isothiazolo[5,4- ]pyridin-3(277)-ones 90b and isothiazolo[5,4-. ]pyridin-3(27/)-thiones 90a, the... 

Phenylpropionic acid derivatives of general formula 261, functionalised at C-2 with a 3-heterosubstituted benzisothiazole, were patented for use in the treatment and/or prevention of peroxysome proliferator-activated receptor gamma (PPARgamma) mediated diseases [89]. Only the synthesis of the 3-sulfur linked compound 264 (40%) was extensively described starting from methyl 3-[4-(benzyloxy)phenyl]-2-chloropropionate (263) and benzoisothiazol-3(2H)-thione (262) operating in the presence of MeONa/MeOH (Scheme 66). 

Isothiazoles are reported to yield the lactam (101) on reaction with diphenyl ketene <85BSB149>. Ethyne dicarboxylate esters add to 2,1-benzisothiazole to generate quinoline esters (102), and benzyne reacts to yield aeridine <83H(20)489, 88JCS(Pl)2l4l>. 2-Methyl-2,l-benzisothiazolin-3-thione with acetylene esters forms 2-iminobenzoquinone methides (103), which dimerize to give diazocines (104) or further react with the ethyne ester to yield diadducts (105). The initial adduct formed with phenylethyne and 2-methyl-2,l-benzisothiazolin-3-thione rearranges to produce l,2-dithiole[3,26]... 

Benzisothiazole 2,2-dioxide is prepared by treating the 2-aminobenzoylsulfonic acid sodium salt with phosphorus oxychloride <86JHC1645>. The sodium dithiocarboxylate (230) on treatment with an acid or iodine gives the 2,1-benzisothiazoline 3-thione (231) <82JOC5255>. 

Chloro- benzisothiazoles (153) or benzisothiazolium (154) salts react with thiolacetic acid to give 1,2-dithioles, and benzo-l,2-dithiole-3-thiones are formed from benzisothiazoline-3-thiones with hydrogen sulfide. An isothiazoline-3-thione (155) reacted with phenylethyne to form what may... 

Boberg et al. (96PS203) described the preparation of the sulfimides 162 and sulfonamides 163 from 2-methyl- or 2-benzyl-l,2-benzisothiazol-3(2//)-thiones 161 by reacting with sodium /V-clilorobenzensulfonamide (Scheme 55). Some sulfimides 162 decomposed at room temperature in the solid state, quickly in solution and especially in polar solvents. Their instability depends on the heterocyclic part of the molecule and also on the substituents in the aryl ring, e.g., electron withdrawing substituents like N02 or Cl stabilized sulfimides 162. 

The general synthesis of 2,1-benzisothiazolium salts consists mainly in the N-alkylation of the corresponding 2,1-benzisothiazole as well in the S-alkylation of 2,1 -benzisothiazol-3(2//)-ones and thiones as well as in O/S-elimination. 

A series of compounds with a 2,1-benzisothiazol-basis were easily available from 2, 1-benzisothiazol-3(2//)-one 180. The treatment of 1-methyl-2, l-benzisothiazol-3 (2//)-one 180 with phosphorus pentasulfide in pyridine gave the 1-methyl 2,1-benz-isothiazol-3(2//)-thione 181 in 28% yield. The preparation of l-methyl-3-methylthio-... 

The 1-methyl-2, l-benzisothiazol-3(2/7)-thiones 181 reacted with sodium /V-chloro-benzensulfonamide 186 to sulfimides 187, sulfinamidinates 188 and to sulfonamides 190 (20-78%). Sulfonamidates 189 were synthesized by an oxidation of sulfimides... 

A-Aryl 3-chloro-l,2-benzisothiazolium chlorides 109 were converted with thio-acetic acid to 3-aryl-imino-l,2-benzdithioles 332. In contrast, N-alkyl salts 109 reacted to form 2-alkyl-l,2-benzisothiazol-3(2//)-thiones 161, which are in equilibrium with 332 (67CB2435, Scheme 110). 

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