Isothiazoles, fused synthesis

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>. 

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 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... 

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 . 

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. 

The well-known synthesis from thiocyanatovinylaldehydes and nucleophiles has been useful for the preparation of substituted isothiazoles and for fused isothiazole systems (see Section 4.05.9.2.1). Enaminothiones and thioanilides represent the starting compounds in a number of procedures based on oxidative cyclization with different reagents. By this method, substituted isothiazoles can be obtained (see Section 4.05.9.1.1), and with high enantiomeric purity starting from chiral reagents (see Section 4.05.9.2.1) <1999JME5402>. 

The weU-known synthesis from 3-halogeno-a, -imsaturated aldehydes 1 and ammonium thiocyanate, via intermediate 2, is very useful for the preparation of substituted isothiazoles 3 and for fused analogues (Scheme 1, Method A) [1,2]. 

The synthesis of the fused isothiazole systems 2,l-benzisothiazolo[2,3-i]-2,l-benzisothiazole, 8-methylbenzo[l,2-c 5-rf ]diisothiazole, and 3-methylbenzo[l,2-c 6,5-rf ]diisothiazole uses the standard reaction of iV-sulfinylmethanesulfonamide with 2-toluidines to obtain the 2,1-benzisothiazole ring <85CJC882, 88JHC1095, 91JHC347>. 

---