5-Substituted isoxazoles, tautomerism

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. 

With 3- and 4-substituted isoxazoles the tautomeric form normally present is the XH tautomer, (13 X = O) and (14 X = O, N) respectively. However, other influences need to be considered as in cycloserine (IS), which exists as a zwitterion, as does 5-amino-3-hydroxy-isoxazole (16). 

Azirines and Aziridines.— The photolysis and thermolysis of the azido ester (143) to the azirine (144) was described by Hassner and Fowler in 1968. A study of isomeric compounds (145) has now been described, leading to the tautomeric isomer (146) of the antibiotic azirinomycin (147). 3,5-Dimethylaminoisoxazoles (148) have been prepared by the addition of hydroxylamine to phosgene iminium salts. The photoisomerization of the 4-substituted isoxazoles (148) to the azirines (149) is already known, and a paper has now described the near-quantitative thermal... 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

Isoxazol-3-ol, 5-methyl- — see Hymexazoi Isoxazoi-5-ones 3,4-disubstituted synthesis, 6, 64 5-substituted tautomerism, 6, 11 synthesis, 6, 64 Isoxazolo[2,3-h][ 1,2]oxazines synthesis, 6, 633 Isoxazolophanes... 

A multiply bonded nitrogen atom deactivates carbon atoms a or t to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (136) and (137). Pyrazoles (136 Z=NH), isoxazoles (136 Z = 0), isothiazoles (136 Z=S), imidazoles (137 Z=NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (137 Z=S) do indeed... 

Attempted metallation of isoxazoles usually causes ring opening via proton loss at the 3- or 5-position (Section 3.4.1.8.6) however, if both of these positions are substituted, normal lithiation occurs at the 4-position (Scheme 36). 2-Lithiooxazoles tend to exist in tautomeric equilibrium with their open chain form. The same is true for l-R-3-lithioindazoles and l-R-5-lithiotriazoles at room temperature. 

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