Isoxazoles reaction with alcoholates

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). 

The opening of the isoxazole ring with a substituent at C-3 proceeds differently and the reaction can take various courses depending on the nature of the substituent. Besides sodium ethylate this reaction has been effected with sodium and potassium hydroxides in alcoholic or aqueous media (see, for instance, references 125 and 142). 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

Reactions of Isoxazoles. The chloroisoxazolium salt (483) activates carboxylic acids for condensation with alcohols and amines.The Lewis-acid-catalysed addition of ammonia to the unsaturated acid (484) yields ( )-homoibotenic acid... 

Efficient and regioselective iron-catalyzed aerobic oxidative reactions afforded 3,5-disubstituted isoxazoles 5 from homopropargylic alcohols 4, r-BuONO as the nitrogen source, and H2O under mild conditions (140L6298).A transition metal-free one-pot synthesis of 3,5-disubstituted isoxazoles used terminal alkynes by treatment with -BuLi, then aldehydes and iodine to afford intermediate a-alkynyl ketones 6 converted into isoxazoles 7 with hydroxylamine (14JOC2049). 

A tetrahydropyranyl linker is an acid-sensitive linker for alcohols. Nitrile oxides were generated in situ from tetrahydropyranyl-linked nitro alkanes and phenyl isocyanate under Mukaiyama conditions, and reactions with various alkynes gave resin-bound isoxazoles (Scheme 11.39). Cleavage with diluted trifluoroacetic acid gave isoxazoles as primary alcohols in a traceless manner. A library of 3-hydroxymethyl-4,5-disubstituted isoxazoles was prepared in a parallel and automated fashion by a 96-well plate synthesizer with an average yield of 60%. 

Preparation of S-Acetylsulfanilamido-S-Methy/isoxazole 0.9 gram of 3-amino-5-methyl-isoxazole in 5 cc of pyridine was allowed to react with 2.0 grams of acetylsulfanil chloride accompanied by the generation of heat. After about one hour, water was added to the reaction mixture and the crystal precipitated out was recrystallized from alcohol to give 2.5 grams of 3-acetylsulfanilamido-5-methylisoxazole, melting point (decomposition) 220° to 221°C. 

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... 

The first demonstration of fluorous synthesis was in the preparation of small (8-12 members) isoxazo-line and isoxazole libraries by the three-step procedure outlined in Figure 8.1461 All reactions were purified by three-phase liquid-liquid extraction. The starting substrates were simple allylic alcohols which were tagged with the fluorous silyl halide 5 to make substrates 6 for an ensuing dipolar cycloaddition. This was conducted by the Mukaiyama method with a large excess of nitro compound and... 

Only a few 1NOC reactions have been run on alkynyl substrates.5152 The reactions do proceed well, as for example, cyclization of the alkynyl nitrile oxide (108), derived in situ from the corresponding oxime.51 The oxime itself was formed in situ by reaction of an a-bromosilyloxime with propargyl alcohol, presumably via a vinylnitroso intermediate (Scheme 32). The alkynyl acylnitrile oxide (109) also cy-clized to afford a bicyclic isoxazole.52... 

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... 

Bicyclic A(0-Mti-homonucleoside analogues such as 591 were synthesized through 1,3-dipolar cycloaddition of an enantiopure 3-hydroxy-l-pyrroline A -oxide and protected allyl alcohol and subsequent introduction of thymine by a Mitsunobu reaction <2003T5231>. Furthermore, isoxazole, isoxazoline, and isoxazolidine analogues of (7-nucleo-sides such as 592-594 were synthesized by 1,3-dipolar cycloaddition of nitrile oxides and nitrones derived from uracil-5-carbaldehydes with suitable dipolarophiles <2003T4733, 2006T1494>. 

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