3- Amino-5-substituted-isothiazole

A reaction model for the S-oxidation of 3-amino-substituted isothiazoles with (-f)- or (—)-((8,8-dichlorocamphor-yl)sulfonyl)oxaziridines (see Section 4.05.55, compound 70) was obtained by B3LYP/6-31G(d,p),S(3df) calculations. Transition states relative energies are in concordance with the experimental reaction outcome and the analysis of the geometrical parameters allows a description of the reasons governing the observed enantioselectivity <2006UP1>. 

The absolute configuration of the sulfur atom in 3-amino-substituted isothiazole A-oxides (see Section 4.05.5.5) was obtained by theoretical calculation of the ECD spectrum and comparison with the experimental ECD curve (see Section 4.05.2.1) <2006UP1>. 

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... 

Azole approach. The substituted isothiazole (142) can be reacted with an ortho ester to form a methyleneamine which reacts with hydroxylamine to yield the 5-oxide (143). With amidines, (142) yields 4-amino derivatives (75JHC883). The reaction of 5-amino-4-ethoxycar-bonylisothiazole with iminoethers results in pyrimidine annulation, as in the formation of... 

Direct lithiation of 3-(Boc-amino)-5-methylisoxazole and 5-(Boc-amino)-3-methylisoxazole gives N/C-dianions which react with a variety of electrophiles to afford 4-substituted aminoisoxazoles in good yields <1996TL3339>. Metallation of 3-substituted isothiazoles <2002JOC2375, 2004JOC1401> and isoselenazoles proceeds satisfactorily at the 5-positions. 

N-Substituted 3-hydroxy-5-arylamino-isothiazole-4-carboxamidines are potent, orally available, in vitro MEKl allosteric inhibitors, <2006BML5561> while amino-heterocycle-substituted isothiazoles are inhibitors of the TrkA kinase in cell assays <2006BML3444>. Benzisothiazolone derivatives are inhibitors of different serine proteases, such as cell tryptase <1998JME4854> and HLE <2003EJM421>. 

The production of chlorinated by-products is largely avoided when A-sul-phinylmethanesulphonamide (MeSOaNSO) is used as the cyclization agent for o-toluidines or A-sulphinyl-o-toluidines, in boiling pyridine. The procedure has been successful in the production of numerous 2,1-benzisothiazoles (including naphth[l,2-c]isothiazole), but failed to yield the hydroxy- or amino-substituted heterocycles from the corresponding substituted o-toluidines. ... 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

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). 

From the results of 4H NMR studies14 and X-ray analysis of 712 the conclusion was drawn that the ground state of substituted 3-amino-benz[d]isothiazole-1,1-dioxides is best represented by structures (7a) and (9a). 

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