Isothiazoles, fused

ISOXAZOLE AND ISOTHIAZOLE FUSED WITH AZINES INTRODUCTION 616... 

Lithiation at C-5 in isothiazoles occurs rapidly with the formation of relatively stable metallated derivatives whereas lithiation at C-3 gives rise to N—S cleavage and nitrile formation. Hence cleavage reactions by base of isothiazoles fused to azines are predictable, especially since the acidity of H-3 is increased in the fused systems. Such cleavage reactions are shown for the quinoline-fused isothiazole (124) (75JCS(P1)2271, 78JHC1527). 

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>. 

Pyrazole-, Thiazole-, and Isothiazole-fused Thiophens and Related Systems.—... 

Isothiazoles Fused to other Nitrogen-containing Heterocycles.—In view of the ease with which, in the laboratory at least, an isothiazole ring may be fused to biological nitrogen heterocycles, it is, perhaps, surprising that no naturally occurring isothiazole has yet been found. Typical recent work includes the efficient synthesis of isothiazolo[3,4-d]pyrimidines (114 X = NHR or SMe), of isothiazolo[4,5-i>l-... 

Usually, N-sulfinyl compounds (59) behave as thionyl transfer reagents, similar to, but milder than, thionyl chloride. For example, o-diamines with A-sulfinylbenzeneamine (59 R = Ph) afford fused 1,2,5-thiadiazoles, as in Scheme 8a.77 The advantage of using Af-sulfinyl compounds, rather than thionyl chloride itself, is that concomitant chlorinations and oxidations are avoided. This is of particular importance in the synthesis of 2,1-benzisothia-zoles (Section V,B,6). Singerman s reagent, N-sulfinylmethanesulfonamide (60) is especially valuable 78 it was used very successfully in the synthesis of a series of benzobis(isothiazoles).79... 

The Diels-Alder reaction between isothiazole-dioxides and various dienes represents an attractive approach toward a range of bi- and tricyclic derivatives containing the fused... 

The 1,3-dipolar cycloaddition of diazoalkanes 276 and nitrile oxides 279 to isothiazole dioxides 275 provides an easy entry into fused bicyclic isothiazole systems 277 and 280, respectively <06JHC1045>. The adducts from 4-bromoisothiazole (R1 = Br) are labile and undergo spontaneous debromination to form the aromatic bicyclic pyrazolo-isothiazoles 278... 

A series of bicyclic isothiazole-S-oxides 8 were prepared by reaction of fused 1,2-dithole-S-oxides 7 with a range of primary amines via an S/N exchange reaction <99JHC161>. 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

Pyrazolo[3,4-c]furazans (71) have been prepared by dehydration of dioximinopyrazolines 70,70 and fused isothiazoles 73 by oxidative cyclization of thioamides 727 following adaptations of standard syntheses of furazans and isothiazoles. 

In contrast, the thiophenone (204) undergoes a stereospecific conrotatory photocyclization via the enol (205) to give cis fused dihydrobenzo[b] thiophen (206).165 Initial nitrogen-sulfur bond homolysis is believed to be responsible for the photoisomerization of isothiazol-3(2//)-ones to thiazol-2(3//)-ones.166... 

Treatment of aryl and heteroaryl o-azidocarbaldehydes with bis(trimethylsilyl)sulfide and hydrochloric acid gave fused isothiazoles, via thionation of the formyl function followed by spontaneous decomposition at room temperature. Yield was dependent upon the nature of the heteroaromatic ring. [94CL1873, 94PS479]... 

There are two series of fused bicyclic compounds incorporating both an isothiazole and a benzene ring. These two ring systems are now generally known as 1,2-benzisothiazole (1) and 2,1-benzisothia-zole (2). 

Fused ring systems can be prepared either from an azine precursor or from an isoxazole or isothiazole precursor. In the sections on synthesis of these compounds the former method is grouped under Azine approach , the latter under Azole approach . 

The ease of nucleophilic substitution in the azine ring is increased after fusion with the azole. Substitution is also possible in the azole ring, especially in the fused isothiazole systems. 

Isothiazole can be fused with pyridine in nine different ways the section on synthesis has been organized accordingly. Further fused systems arise from the diazines, the triazines and their areno and heteroareno homologues. 

As pointed out, the 3-position in fused isothiazoles is activated for nucleophilic substitution. Amino groups in activated azine positions after diazotization are frequently displaced by the anion of the acid used in the diazotization reaction. Similarly, this type of reaction can be used to substitute the 3-amino group in (118) with a bromine substituent (73CJC1741). 

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