The kinetics and mechanism of the electrophilic substitution of heteroaromatic compounds. Part XXXVIII. Hydrogen exchange of isoxazoles and isothiazoles

Five‐Membered Heterocycles: 1,2‐Azoles. Part 2. Isoxazoles and Isothiazoles

“…The high reactivity of the 5-position can be due not only to the electron distribution in the ground state but also to the stabilization of the formed anion by the s-3d (sulfur) bonding. A similar study with isoxazoles provided the same conclusions [36,38].…”

“…The structure of the bioactive natural compound triumferol (36) has also been established as a 4-hydroxy-derivative by 1 , has also been isolated from Amanita muscaria and from Amanita pantherina [62]. Brassilexin (38a) and sinalexin (38b) are phytoalexins, with fungicidal activity, isolated from the leaves of Brassica juncea (Cruciferae) [69,70].…”

“…The positional selectivity in the electrophilic attack on heterocyclic molecules can be explained according to the magnitude of the HOMO electron density of each atomic center [35], which predicts the reactivity order of electrophilic substitution of isoxazole (1) as C4 > C5 > C3, in agreement with the experimental data. Comparison of partial rate factors of isothiazole (2) with those of benzene and related compounds shows that its 4-position is $10 4 times more reactive towards electrophiles than expected on the basis of the calculated p-electron density at carbon atoms and the electronegativity of the heteroatoms [36]. This indicates that when attempting to correlate the theoretical calculations with chemical reactivity one must be careful and consider whether ground or excited states are involved, or whether it is the electron density of intermediates, rather than the original molecule, that determines the product of a chemical transformation.…”

Step-by-Step Multifunctionalization of Isoxazoles Based On SEAr Reactions and C–H Direct Arylations

“…15 Treatment of 1 with NH 4 NO 3 in the presence of TFA afforded 13 in moderate yield (47%) as shown in Scheme 7. The obtained 13 was reduced to afford 4-aminoisoxazole (17).…”

“…In detail, Johnson, Katritzky, and co-workers investigated the acid-catalyzed hydrogen exchange rates of isoxazoles using D 2 SO 4 to determine their relative reactivity towards electrophiles. 17…”