Isoxazoles pyridine ring

In a paper concerned with the synthesis of fused pyridazines, the isoxazole 13 was used as a masked amino alcohol, which was eventually used to construct a fused pyridine ring. A standard hydrazine reaction, followed by hydrogenolysis of the isoxazole of the intermediate... 

In a series of substituted 2-arylpyrrolidines in which the substituted aryl group is a bio-isosteric replacement for the pyridine ring of nicotine, it was found that the isoxazole derivative (69) is a potent cholinergic channel activator (116). 

Isoxazole and Isothiazole Derivatives. Bioisosteric replacement of the pyridine ring in nicotine generated a series of novel isoxazole compounds that are selective and potent neuronal nAChR agonists, as exemplified by ABT-418 (71) (Table 14.8) (299). Among the variety of substituents examined at C3 cf the isoxazole, methyl turns out to be optimal, even though other substituents, such as C2-C4 linear alkyl, CF Br, and benzyl (not phenyl), still provide potent analogs. The 3-des-methyl... 

Cadman, E.D., Raszkiewicz, J.L., Sullivan, J.P., Arneric, S.P., 1994. Ligands for brain cholinergic channel receptors synthesis and in vitro characterization of novel isoxazoles and isothiazoles as bioisosteric replacements for the pyridine ring in nicotine. J. Med. Chem. 37, 4455-4463. 

Palladium-carbon triethylamine Pyridine ring from 4-(3-keto)isoxazoles... 

The reaction of a dibromochalcone with hydroxylamine hydrochloride in pyridine gave three products with the expected 2-isoxazoline product as the predominate compound. A ring bromination product and an isoxazole were also isolated (70UC796). The reaction of hydroxylamine with /S-thiosulfates of propiophenone at reflux produced 3-phenyl-2-isoxazo-line (455). At room temperature a bis-Michael product (456) was produced. The reaction with N -phenylhydroxylamine yielded a mono-Michael type product (457) (74CPB1990). 

The mechanisms of the electrophilic substitutions in the isoxazole nucleus have not yet been studied. They should not differ fundamentally from those usually accepted for the substitution of aromatic systems but the structural specificity of the isoxazole ring might give rise to some peculiarities, as recently specially discussed.One important point is that isoxazole shows a clearcut tendency to form coordination compounds. Just as pyridine and other azoles, isoxazoles coordinate with halogens and the salts of heavy metals, for example of cadmium,mercury,zinc. Such coordination... 

No direct nucleophilic substitution of the hydrogen atoms in the isoxazole nucleus a or y to the nitrogen is as yet known. Thus, the Chichibabin reaction fails in the isoxazole series because of the cleavage of the heterocyclic nucleus under these conditions. It is the lability of the isoxazole ring toward nucleophilic reagents that makes the chemical behavior of isoxazole fundamentally different from that of pyridine. 

As already noted, the lability of the isoxazole nucleus toward the action of nucleophilic agents distinguishes this heterocyclic system from those of other azoles and of pyridine. The conditions which lead to ring opening, and the products of ring cleavage are quite varied and depend on the position and the nature of substituents, although it is invariably the N—0 bond which is broken. 

Quatemization of the isoxazole nitrogen atom makes the ring particularly susceptible toward nucleophilic attack there is a certain analogy here with pyridine. The cleavage of the ring proceeds extremely readily in quaternary salts of isoxazole, even occurring by the action of such weak nucleophilic agents as the anions of carboxylic acids. 

Only a few of such reactions of these rings have been reported since CHEC-II(1996). However, Weaver and Tennant <1999TL8157, 2000TL9319> have demonstrated that imidazo[4,5-f]isoxazoles such as 19 undergo thermally driven reactions with acetylenic diesters (such as 22) to yield, rather than the expected bridged bicyclic compound 20 or the pyridine Woxide 21, the 2-pyrrol-2-ylimidazole 24 which the authors suggest proceeds via loss of a methyl oxalate unit. The proposed pathway is outlined in Scheme 1. 

No further advances in the synthesis of isoxazolo[5,4-. ]pyridines by closure of the isoxazole ring have been reported since the original chapter in 1996CHEC-II(7)283. 

In an interesting reaction, the oxazolo[3,4-6]pyridine (598) was converted to the pyrazolo[3,4-6]pyridine (599) (70%) by heating at reflux in a mixture of aniline, ammonium acetate, and glacial acetic acid for 2 h <9lPS(63)ll9>. The authors propose that the reaction proceeds by ring opening of the isoxazole ring by aniline with the formation of a phenylhydrazino intermediate which then cyclizes (Equation (61)). 

Isoxazolo[4,5-c]pyridines have been converted into thiazolo[5,4-(>]pyridines by three methods. Catalytic hydrogenation of compound (616) using palladium on carbon (10%) in aqueous sodium hydroxide at 50 psi followed by neutralization with HC1 to selectively cleave the isoxazole ring afforded 6-chloro-3-(l-iminoethyl)-4-hydroxypyridine-2-thione (617) (57%) <90JCS(P1)1477>. Animation of the thione moiety of the imine (617) with hydroxyamine-Osulfonic acid and subsequent cyclization affords 6-chloro-4-hydroxy-3-methylisothiazolo[5,4-<5 pyridine (618) (57%) (Scheme 78). 

Chart 1 Ring systems formed by fusion of isoxazole or isothiazole with pyridine (Z = O, S)... 

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