Isoxazolium salts synthesis

Isoxazoles are susceptible to attack by nucleophiles, the reactions involving displacement of a substituent, addition to the ring, or proton abstraction with subsequent ring-opening. Isoxazolium salts are even more susceptible to attack by a variety of nucleophiles, providing useful applications of the isoxazole nucleus in organic synthesis. Especially useful is the reductive cleavage of isoxazoles, which may be considered as masked 1,3-dicarbonyl compounds or enaminoketones. 

The smooth conversion of the enol acetate (151) into an A -acyl derivative (152) under extremely mild conditions points to the high acylating capacity of these esters. This cleavage of isoxazolium salts is also caused by other anions of carboxylic acids, and thus they can be readily converted to reactive enol esters. A very convenient and specific synthesis of peptides due to Woodward et is based on... 

This isoxazolium salt (10 g.) (obtained from the Aldrich Chemical Company, Inc.) was dissolved in 45 ml. of aqueous 1 M hydrochloric acid and reprecipitated by the slow addition with swirling of 400 ml. of acetone. The salt was collected, washed with 300 ml. of acetone, and dried overnight at 25° under reduced pressure (< 1 min.) to give a fluffy product, m.p. 206-208° (decomp.). An isomeric salt, A-ethyl-5-phenylisoxazolium-4 -sulfonate, which may be obtained by the usual synthetic procedure,2 is also useful in peptide synthesis. 

In a survey of the methods used for peptido synthesis in 1968, the isoxazolium salt method was used in 7% of the examples surveyed J. H. Jones in Amino Acids, Peptides, and Proteins, Vol. 2, The Chemical Society, London, 1970, p. 145. 

Isoxazolin-5-one, 2,3-dimethyl-4-substituted photolysis, 6, 14 Isoxazolinones synthesis, 5, 132 Isoxazolin-3-ones alkylation, 6, 43 synthesis, 6, 106, 129 Isoxazolin-4-ones synthesis, 6, 106-107 Isoxazolin-5-ones alkylation, 6, 39 4,4-dialkyl substituted reaction with Grignard reagents, 6, 40 reactions with bases, 6, 41 synthesis, 6, 103-105 Isoxazolium bisulphate, 2,3,5-trimethyl-hydrogen exchange, 6, 21 Isoxazolium salts deprotonation, 5, 71 as hardeners for gelatin, 1, 363 nucleophilic cleavage, 6, 31 nucleophilic reactions, 6, 28-29 4/f-pyran synthesis from, 3, 761 reactions... 

When recent advances in the chemistry of isoxazoles were reviewed by Kochetkov and Sokolov1 in this Series in 1963 (and by Quilico2 in 1962), the main features of isoxazole chemistry had been established. Since then some important new discoveries have been made, but probably the most significant advances have concerned the exploitation of the known features of their chemistry in synthesis. Particularly noteworthy developments include the further application of the cycloaddition of nitrile oxides in the synthesis of isoxazoles (Section II,C and D), the use of isoxazolium salts in peptide synthesis (Section III,B,2), syntheses involving the products of reductive cleavage of isoxazoles as intermediates (Section III,D and E) and annelation reactions via deprotonation of alkylisoxazoles (Section 1II,E). 

Isoxazolium salts can be prepared by appropriate general methods, although the low basicity of the isoxazoles and their sensitivity to nucleophilic attack may necessitate special care. The explosive nature of isoxazolium perchlorates must be noted.125 The preparation of isoxazolium salts containing bulky N-substituents can be very difficult, and the particular utility of such compounds in synthesis (see Section III,B,2) has prompted the development of new methods for preparing them. A noteworthy route involving the reaction of the isoxazole with a carbenium ion, formed from a suitable alcohol, is exemplified in Eq. (18).30,126... 

Isoxazolium salts are even more susceptible than isoxazoles to attack by nucleophiles. It was discovered in the early years of this century that 3-unsubstituted isoxazolium salts were cleaved by a variety of mild reagents, including even carboxylate ions in aqueous solution.1,165 However, it was not until much later that the Harvard group were able to elucidate details of the structures of the products and the routes by which they are formed, and to exploit the reactions, notably in peptide synthesis. 

Synthesis of 3-isoxazoline is accomplished only from quaternary salts oximation of flavyUum salts, nucleophilic attack on and basic treatment of 2-isoxazolium salts. Earlier literature on the synthesis of 3-isoxazoline is systematically comprehended <84CHEC-I(6)1,9IHC(49)i>. 

In general, synthesis of 4-isoxazolines is accomplished via three routes 1,3-dipolar cycloaddition of nitrones to alkynes or by the oximation of a,i -ethylenic ketones, a-alkynic ketones and aldehydes or from the selective reduction of isoxazolium salts. The nitrone (262) underwent tandem cyclo-addition-[2,3]sigmatropic rearrangement with allenyl sulfoxide (263). And it resulted in 4-isoxazoline (264) (Equation (46)) <89TL663>. 

The application of isoxazolium salts as reagents for activating carbonyl groups in peptide synthesis is based on this reaction [85]. 

Based on this reaction is the application of isoxazolium salts as COOH-activating reagents in peptide synthesis [303]. 

The isoxazolium salt has been used in the synthesis of other difficult peptide structures. A peptidoglycan has been obtained in good yield by this procedure (eq 5). ... 

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