Isoxazolium ring

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). 

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. 

Isoxazolium salts with active methylene compounds can undergo ring expansion thus (175) with MeC0CH2C02Et gives the 4-pyridone (176). 

V-Alkylbenz[base-catalyzed ring expansion to 1,3-benzoxazines (305 — 306 — 307) (Section 3.4.3.12.3). Benzoxazinones are obtained by heating 3-acylanthranils... 

Ring expansion of isoxazolium salts (168), by treatment with sodium hydroxide, can be used to synthesize both 2H- 1,3-oxazines and 2H- 1,3-benzoxazines. The reaction probably involves an ylide intermediate (Scheme 59) (62CJC882). 

The 2//-l,3-oxazine ring was first described by King and Durst202 who revised earlier work of Kohler and Blatt203 and established that the anhydro compounds formed by the action of alkalis on isoxazolium salts are 2H-1,3-oxazines (66) [Eq. (52)]. The same ring system is obtained from an a-cyano-a-bromo ester with triisopropyl phosphite through an... 

The A pyrroline-A-oxides (SO) undergo violently exothermic reactions with DM AD in the absence of solvent.95 In ether at room temperature, unstable products (51) that rearrange exothermically to the pyrrolines (52) are formed this ring fission recalls that of isoxazolium salts.96 With unsymmetrical acetylenes, two modes of cycloaddition are possible. Propiolic acid adds to 50 (R = H), giving an unstable solid... 

Dioxo-J2-pyrrolines (33) have been obtained from isoxazolium salts (32) by the action of alkali cyanides followed by ring-opening and reclosure.193... 

Bicyclic isoxazolines obtained by 1,3-dipolar cycloaddition of 1-pyrroline A-oxides with DMAD undergo ring fission at room temperature to give pyrroline derivatives (equation 2) (66CC607). This ring fission is similar to that of isoxazolium salts but requires no external nucleophile (61JA1007). 

Ring opening of the cycloadducts 234 from oxazoles 232 and dienophiles 233 gives dihydropyridines 235 and frequently pyridines 236 entities such as XR3, HR3, or XOH can also be lost in the aromatization of intermediate 235. Isoxazolium salts with active methylene compounds can undergo ring expansion thus, isoxazolium salt 237 with acetoacetic ester gives the 4-pyridone 238 (Scheme 132) . 

The isoxazolium and benzisoxazolium cations also undergo base-catalyzed ring-opening reactions (e.g., 87 - 89), however, such reactions appear to... 

It is often difficult to identify reactions involving addition to the ring if they are rapidly followed by elimination or ring cleavage. The only examples where the products of simple nucleophilic addition have been isolated involve isoxazolium salts. 

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... 

Unsubstituted isoxazolium salts reacted with borohydride to give isoxazolines (68) (and their borane complexes) 3-substituted-5-unsubstituted isoxazolium salts gave isoxazolines and, finally, isoxazolidines.181 Most other nucleophiles (e.g., ethoxide, hydroxide, and amines) gave only products of ring cleavage, though in the case of piperidine and morpholine the adducts 69 could be isolated at low temperatures.180 It is thus possible that in these... 

Some reactions of 2,3,4-trisubstituted isoxazolium salts (exemplified by 70) leading to ring transformations, are summarized in Scheme 14.180 Other active methylene compounds such as ethyl acetoacetate and cyano-acetamide give analogous results to those with diethyl malonate products of base-induced ring opening by ethoxide are also obtained. When the reaction with phenylhydrazine is carried out in the presence of sodium hydroxide in ethanol the product is 71, presumably formed via the im-inoketene 72. 

A particularly useful application of the types of reaction described above is the formation of a ring by intramolecular base-induced condensation of a methylisoxazole (or isoxazolium salt) with a conveniently placed carbonyl function. The required starting materials are often conveniently prepared from the 4-chloromethyl derivatives.236 The initial products can undergo various transformations via cleavage of the isoxazole ring. One of the earliest examples, which illustrates the principles well, is shown in Scheme 28. 

The reduction of isoxazolium salts with metal hydrides is also not entirely predictable, and here the progress of the reaction depends on (i) the reagent, (ii) the solvent, and (Hi) the ring substituents. Generally, isoxazolium salts (119) on reduction with sodium borohydride in aqueous acetonitrile give 4-isoxazolines (120), their borane complexes, 3-isoxazolines (121), isoxazolidines (122), and minor amounts of 3-hydroxypropylamines (123). In some cases, however, particularly if the substituent group at C-3 is aryl and the reaction is carried out in ethanol rather than acetonitrile, the major products are... 

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