Isoxazolium salt

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). 

Unsubstituted isoxazolium salts (247) lose the 3-proton under very mild conditions, e.g. at pH 7 in aqueous solution, to give intermediate acylketenimines (248) which convert carboxylic acids into efficient acylating agents (249) (79AHC(25)147). 

Isoxazolium salts react with enamines to give pyridinium salts (Scheme 33) (69CPB2209). 

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 can be prepared by reaction with alkyl iodides or sulfates, although the low basicity of isoxazoles and their sensitivity to nucleophilic attack may necessitate special care. Isoxazolium salts containing bulky Af-substituents can be prepared by the reaction of isoxazoles with alcohols in the presence of perchloric acid. For example, the reaction of 3,5-dimethylisoxazole (53) with some alcohols in the presence of 70% perchloric acid gave isoxazolium salts, (54a) in 29%, (54b) in 57% and (54c) in 82% yield 79AHC(25)147, 68JOC2397). Attempts to quaternize 3,5-dimethyl-4-nitroisoxazole failed 71JCS(B)2365). 

Sodium borohydride and 3-isoxazolium salts with a 3-unsubstituted position also give isoxazolines, as do the 3-substituted 5-unsubstituted derivatives. With the latter group, further reduction occurs to the isoxazolidines (74CPB70). 

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). 

Treatment of 7V-benzyl-l,2-benzisoxazolin-3-one with base produced a benzoxazine-4-one (see Scheme 88). The base catalyzed rearrangement of the 2-methyl-3-phenyl-l,2-benzoisoxolium salt to an oxazine is believed to proceed via a similar intermediate (67AHC(8)277). A number of other decompositions could possibly proced via this proposed route (74HCA376, 67AHC(8)277), which has also been postulated for the rearrangement of a variety of isoxazolium salts, e.g. the conversion of (200) into (202) (Section 4.16.3.3.2(i)(b)). 

This small class of compounds is characterized by an N-alkyl moiety, and they are synthesized from isoxazolium salts by isomerization or by the dehydration of 2-alkyl-isoxazolidin-3-ols (Scheme 128) (74BSF1025). The reaction of isoxazolium salts that are unsubstituted in the 5-position with phenylmagnesium halides was reported to give 3-isoxazolines by 1,4-conjugate addition, and this reaction is also shown in Scheme 128 (74CPB70). 

Isoxazolium salts, 2,4-dimethyl-5-phenyl-nucleophilic reactions, 6, 28 Isoxazolium salts, 3,5-distyryl-reactions, 6, 51... 

Isoxazolium salts, 2,3,5-trimethyl-condensation reactions, 6, 50 nitration, 6, 22 3-Isoxazolium salts nucleophilic reactions, 6, 29 Isoxazoloazines fused... 

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. 

Since the initially formed enol ester rearranges slowly to an imide,3 the yield depends on the rate at which the isoxazolium salt reacts, and that rate is increased by vigorous stirring. The reaction time for the activation step is approximately 8 minutes in nitromethane at 25° and approximately 1 hour in acetonitrile at 0°. In reactions performed with acetonitrile as the solvent, the checkers did not obtain complete solution. The reaction flask should be kept in a water bath to minimize heat transfer from the magnetic stirrer to the reaction mixture. 

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. 

Glutamic and aspartic acid Isoxazolium salts, carbodiimides... 

Chances may be better, however, when a cyclic starting material includes the acyl group R4—CO. Here, the pathway based on Meldrum s acid was proven very useful [87JCS(P1)1177, 87TH1]. De Shong et al. started with R4-substituted isoxazoles (83JOC1149). The isoxazolium salts, obtained from ethyl bromoacetate, convert into /3-ketoamides, where best results were observed in two-phase systems. These /3-ketoamides cyclized to 3-acyI-tetramic acids by adding base. (See Fig. 13.)... 

Conversion of isoxazolium salts by the action of alkali cyanides into 4,5-dioxo-A2-pyrrolines [184, 185]. 

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

Unsubstituted isoxazolium salts (72) react with hydrazines to yield 3-aminopyrazoles (73 X = H, N02, Hal, COMe, C02Et, R3 = H, Me, Ph, CONH2) (88S203). 

Isoxazolium salts (3) serve as condensing agents in the direct formation of amide links between the free amino and carboxyl groups on gelatin (Scheme 2) (65MI11400). 

Isoxazolium salts, such as the well-known Woodward s Reagent K , have found significant use as reagents in the preparation of activated enol esters suitable for peptide coupling reactions. Since this aspect of isoxazole chemistry has been extensively surveyed, this topic will not be treated in further detail here (B-74MI11601). 

The reaction of an enamine with the isoxazolium salt (162) leads to a fused 4-iminopyran, probably via the route indicated in Scheme 24 (68JOC867). 

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). 

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... 

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