Isoxazolium ions

Some examples of the isoxazolium ions which have been tried as peptide coupling reagents are compounds 56-59. The sulfonium inner salt 56 (Woodward s Reagent K) is widely used because the by-product (60) in Scheme 10 is water soluble it is stated to be superior to diimides as far as racemization is concerned.168,170,171 (V-Arylisoxazolium salts such as 57... 

In contrast, quaternary 5-aryl-isoxazolium ions 4 with free 3- and 4-position are cleaved... 

Cationic rings are readily reduced by complex hydrides under relatively mild conditions. Thus isoxazolium salts with sodium borohydride give the 2,5-dihydro derivatives (217) in ethanol, but yield the 2,3-dihydro compound (218) in MeCN/H20 (74CPB70). Pyrazolyl anions are reduced by borohydride to pyrazolines and pyrazolidines. Thiazolyl ions are reduced to 1,2-dihydrothiazoles by lithium aluminum hydride and to tetrahydrothiazoles by sodium borohydride. The tetrahydro compound is probably formed via (219), which results from proton addition to the dihydro derivative (220) containing an enamine function. 1,3-Dithiolylium salts easily add hydride ion from sodium borohydride (Scheme 20) (80AHC(27)151). 

The reactions of 3-unsubstituted iso.xazolium salts (123) with hydroxide, alkoxide, cyanide and azide ions have also been studied, and they can in general be rationalized in terms of the ketoketenimine intermediate (124). The results of these reactions are summarized below. The application of such reactions to 3-unsubstituted isoxazolium salts bearing substituents other than alkyl and aryl groups has received little attention, but 5-aminoisoxazolium salts have been studied (74CB13). 

Ions such as isoxazolium and pyrazolium are produced by protonation of a multiply bonded nitrogen in the above species, and are therefore present under acidic conditions. Similar cations can be formed by alkylation. 

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. 

The establishment of the main features of the reactions of carboxylate ions with 3-unsubstituted isoxazolium salts is fully described in the classic paper by Woodward and Olofson.165 A generalized reaction scheme is shown as Scheme 10. Deprotonation at the 3-position is rapidly followed (or more probably accompanied) by ring opening to give the ketoketenimine (54). Ketoketenimines have been detected spectroscopically and are sufficiently stable for isolation in some cases.166,167 Reaction of carboxylic acid... 

Nucleophiles other than carboxylate ions have been less widely studied in reactions with 3-unsubstituted isoxazolium salts, but they can in general be rationalized in terms of the ketoketenimine intermediate. Examples are shown in Scheme 12. Many of these reactions were recorded in the earlier literature, but the structures of the products were in some cases not established until spectroscopic methods became available.165 The application of... 

Benzisoxazoles (91) on treatment with Vilsmeier reagent (DMF/POCI3) resulted in ring cleavage product (92) (Equation (18)) <87TL955>. By photolysis of 1-/-butyl-3,5-dimethyl-2,l-benz-isoxazolium tetrafluroborate (93), nitrenium ion (94) is produced (Equation (19)) <94TL4943>. 

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