1,2-Benzisothiazoles

1-Benzisothiazoles (51) are available from the reaction of thionyl chloride with o-alkylbenzeneamines (o-toluidines).63 Chlorinated by-products are 

1- benzisothiazoles where so much is known about the one and so little about the other. The reason here is the fact that the former is the parent compound of saccharin, whereas the latter has not been very leadily accessible. However, a few contributions to the chemistry of 2,1-benz-isothiazole have recently appeared. 

1- 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.  

7-Acetyl-3-methyl-2,l-benzisoxazole (123) is converted (75%) into the corresponding 2,1-benzisothiazole (125) by the action of phosphorus pentasulphide in boiling pyridine. Its production is rationalized in terms of the initial formation of the thioacyl compound (124), which undergoes valence tautomerism to (125).  

Bambas, The Chemistry of Heterocyclic Compounds , Interscience, New York, 19S2, devotes one page to 2,1- and some 120 pages to 1,2-benzisothiazoles. 

The chemistry of both 1,2- euid 2,1-benzisothiazoles (benzo-[d]- and -[c]-isothiazoles) has been the subject of a comprehensive review. Developments of the past 20 years were emphasized for 1,2-benzisothia-zoles, previous work having been covered by Bambas monograph of 1952. Little was known concerning 2,1-benzisothiazoles before that time, so that the new account is the first definitive review of this subject. The section on saccharin (3-oxo-2,3-dihydro-l,2-benzisothiazole 1,1-dioxide) in Bambas book has also been updated by the appearance of a detailed review on the chemistry of this and related compounds, thus providing a complete survey of this section of the chemistry of 1,2-benzisothiazole. 

The majority of the contributions during the present period of review have dealt with the application and extension of existing synthetic methods. 

Extensive series of l,2-benzisothiazole-3-carboxylic acid derivatives of type (75), (76), and (77), as well as naphtho[2,3-d]isothiazolyl-3-acetic 

In view of the versatility of 3-methylbenzothiazol-2-one hydrazone as a starting material for producing heterocyclic azo-compounds by oxidative coupling, the isomeric 2-methyl-l,2-benzisothiazol-3-one hydrazone has been synthesized (from the corresponding 3-chloro-derivative), and its coupling with dimethylaniline and l-hydroxy-2-naphthoic acid anilide has been examined,  

2- Benzisothiazole l,l-I ioxides.—A series of 5-amino-6-carboxy-3-phenyl- 

Synthesis.—Several new methods of preparing 1,2-benzisothiazoles have been reported. Ultimately, they all involve the cyclization of an arylsulphenamide incorporating an ortho-caxhonyl function. 

the novel method of producing sulphenimines from diaryl disulphides, silver nitrate, and ammonia, applied to bis(2-acetyl-4-methyIphenyl) disulphide (46), affords 3,5-dimethyl-l,2-benzisothiazole (47) directly, in 30% yield.  

A general synthesis of 2-substituted l,2-benzisothiazolin-3-ones from 2-mer-captobenzoic acid involves esterification, halogenation to the sulphenyl halide, conversion into the sulphenamide, and cyclization with a strong base. The synthesis of 3-oxo-3/f-l,2-benzisothiazole 1-oxides by the action of hydrazoic acid on 2-sulphinylbenzoic acids has been extended (see Vol. 2, p. 579). 2-SuI-phinylbenzamides (48) react with hydrazoic acid in polyphosphoric acid to give 3-imino-3//-l,2-benzisothiazole 1-oxides (49) together with the related 5 S -dioxide and l,2-benzisothiazolin-3-one. The preparation of a number of functional derivatives of (49), and an unusual alkaline ring-scission to (50), were also described.  

Mass Spectra.—Detailed fragmentation patterns have been proposed for 

2- benzisothiazoles and the mass spectra compared with those of 1,2-benziso-selenazoles and the corresponding benzothiazoles. The parent compound, 

The literature was surveyed up to the end of 1970 some additional material on 2,1-benzisothiazoles originating from the author s laboratory and presently in course of publication has also been included. A few references to work published in 1971 have been added while this article was in proof. 

Almost all the syntheses presently known require as a precursor an aromatic sulfur-containing compound with a functionalized carbon atom ortho to the sulfur. The general pattern of these syntheses is thus either from 3 or 4 to 1,2-benzisothiazole (1). This 

The parent compound (1) was first prepared in 1923 by Stolle and co-workers.2,3 They found that treatment of thianaphthenequinone (5) with aqueous ammonia and hydrogen peroxide afforded 1,2-benzisothiazole-3-carboxamide (6), which was hydrolyzed to the acid (7) and the latter decarboxylated. 

The formation of an isothiazole ring from the thiophene system (5) is of interest. Probably ammonia breaks the sulfur-carbonyl bond and then adds to the second carbonyl group, giving an imine (8), which is then oxidized by the hydrogen peroxide. A number of similar rearrangements and interconversions of isothiazole, thiophene, and dithiole systems are known and will be discussed later (Section II,C,3). 

Sulfur-nitrogen bonds are readily formed by oxidation of imino-thiols such as 8, and this method is a useful one in the preparation of isothiazoles generally. A further example is given below. 

The novel zwitterion (33), formed by the reaction of cyclohexanone with a mixture of sulphur, carbon disulphide, and ammonia, reacts with aldehydes R CHO to give (34 R = H) and with more carbon disulphide to give (34 R R = S).  

l-Benzisothiazol-3-ylacetic acid and its methyl and ethyl esters, e.g. (72 R = CH2C02Me), have been prepared. Rates of rearrangement of benziso-thiazolyl benzoate (73) to benzoxazinone (74) were determined spectro-photometrically at 25 C. The curves are characteristic of an autocatalytic reaction. Adding sulphur produces a 1000-fold acceleration in the rate. 

6 Other Condensed Ring Systems incorporating Isothiazole 

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Fig. 1. HeterocycHc amines usedia azo dyes, (a) 2-Amino-6-nitrohenzothiazo1e [6285-57-0], (b) 3-amiao-5-nitro-2,l-benzisothiazole [14346-19-1], (c) 3-amiQo-4JT-l,2,4-triazole [65312-61 -0], (d) 5-amiQo-l,2,4-thiadiazole [7552-07-0, (e) 4,4 -diamiQo-2,2 -biphenylsulfone [6259-19-4], (f)...

Couplers which form scarlet dyes with 4-nitroani1ine and red dyes with 2-amiQO-6-nitrobenzothiazole yield blue dyes with 3-amiQo-5-nitro-2,l-benzisothiazole [14346-19-1]. 

In contrast to thiazoles, certain isothiazoles and benzisothiazoles have been directly oxidized to sulfoxides and sulfones. 4,5-Diphenyl-l,2,3-thiadiazole is converted by peracid into the trioxide (146). Although 1,2,5-thiadiazole 1,1-dioxides are known, they cannot be prepared in good yield by direct oxidation, which usually gives sulfate ion analogous to the results obtained with 1,2,4- and 1,3,4-thiadiazoles (68AHC 9)107). 

There are many related examples which are now known as the general Dimroth rearrangement. For example, 3-ethylamino-l,2-benzisothiazole (419) is in equilibrium in aqueous solution with the 2-ethyl-3-imino isomer (420) <72AHCf 14)43). Dimroth rearrangements are known in the 1,2,4-thiadiazole series (421- 422), and in the 1,3,4-thiadiazole series as products of reactions of halogeno-l,3,4-thiadiazoles see Section 4.02.3.9.1 <68AHC(9)165). For a similar example in the 1,2,3,4-thiatriazole series, see Section 4.02.3.1.9. 

X-Ray diffraction studies have been carried out on other 1,2-benzisothiazoles (72JCS(P2)2125, 74CSC535, 76G769) and complexes of substituted 1,2-benzisothiazoles with... 

Table 8 NMR Chemical Shifts of 2,1-Benzisothiazoles in CDCI3 <75CJC836)...

There is very little published information on the UV spectra of 1,2-benzisothiazoles, though more data are available on the 2,1-isomers. The spectra are complex with as many as six maxima above 200 nm. Representative wavelengths of maxima are collected in Table 12. In all cases the most intense bands (e > 15 000) are those at short wavelengths, but all the bands indicated in the table have molar absorptivities greater than 4000, except those of 3-amino-2,l-benzisothiazole. Saccharin absorbs weakly at 350 nm and 277 nm, with intense bands below 230 nm (ethanol solvent) (82UP41700>. It exists as the anion except in acid solutions. The UV spectra of cations formed from 3-amino-2,l-benzisothiazole are discussed in (69CB1961>. Further applications of UV spectroscopy in studying tautomeric... 

Table 12 UV Absorption Maxima of Benzisothiazoles (solvent ethanol or methanol)...

The exoeyelie earbonyl group of isothiazol-3-ones absorbs in the region 1610-1660 em <7lJHC59l). 2-Methylisothiazol-3-one itself has the C=0 and C=C bands at 1660 and 1629 em respeetively, in CCI4 solution <64TL1477). The low earbonyl frequeney is due in part to eontributions from the resonanee form (20b). The earbonyl frequeney inereases in sulfoxides (1660-1730 em ) and 1,1-dioxides (1690-1740 em ) where sueh forms are not favourable. Sulfoxides (1060-1190 em ) and sulfones (1330-1360 and 1150-1190 em ) absorb in the regions expeeted (e.g. saeeharin, 1353 and 1162 em ), but resonanee forms related to (13) eause a reduetion of the frequeney of the asymmetrie SO2 vibration to near 1280 em (70CB3166). A similar situation arises in 3-amino-1,2-benzisothiazole 1-oxides. 

Table 14 Melting and Boiling Points of some Isothiazoles and Benzisothiazoles ...

Data are given for substituents in the 4-position of isothiazole and the 3-position in the benzisothiazoles, except where indicated. Boiling points of liquids (at 760 mmHg) are given in brackets. 

All data for benzisothiazoles taken from (72AHC(14H3). 

Isothiazole behaves as a typical stable aromatic molecule. Thermolysis of substituted isothiazoles at 590 °C leads to the formation of thioketenes (80MI41700) and phenyl-isothiazoles undergo photoisomerism (Section 4.17.6.2) (73BSF1743, 81T3627). 1,2-Benzisothiazole boils at 220 °C without appreciable decomposition, and the 2,1-isomer... 

Annular tautomerism does not occur in isothiazoles or benzisothiazoles. Substituent tautomers can sometimes be distinguished by chemical methods, but it is important that reaction mechanisms and the relative rates of interconversion of tautomeric starting materials or isomeric reaction products are carefully investigated. Physical methods only will be considered in this section, and references to original publications can be found in a comprehensive review (76AHC(S1)1). 

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). 

Benzisothiazoles suffer straightforward ring cleavage, but their 1,1-dioxides, 2,1-benzisothiazoles and derivatives of saccharin give products containing no sulfur. 

Isothiazoles and 2,1-benzisothiazoles are stable to most nucleophilic reagents, but quaternized compounds are dequaternized and/or suffer cleavage of the N—S bond. 

Benzisothiazoles also suffer N—S bond cleavage, following attack at sulfur, but 1,2-benzisothiazole 1,1-dioxides are cleaved at the C—N bond. Saccharin derivatives are attacked at the carbonyl function. In cases where N—S bond cleavage occurs, recyclization can sometimes occur, often producing thiophene compounds. 

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