Isoxazoles chloromethylation

Imidazoles are hydroxymethylated by CH2O at the 4-position 1-substituted imidazoles react at the 2-position. Isoxazoles can be chloromethylated in the 4-position (63AHC(2)365). 

It is only recently that the chloromethylation reaction, well known in the benzene series, has been extended to isoxazoles. It has been thereby found that this reaction results in 4-chloromethyl derivatives (69), their yield decreasing as follows 5-phenyl > 3,5-dimethyl > 5-methyl > 3-methyl isoxazoles > isoxazole. To prove the position of the chloromethyl group these compounds were oxidized to the known isoxazole-4-carboxylic acids (70). It is especially noteworthy that pyridine and its homologs do not undergo chloromethylation. 

Nucleophilic substitution of the halogen atom of halogenomethylisoxazoles proceeds readily this reaction does not differ essentially from that of benzyl halides. One should note the successful hydrolysis of 4-chloromethyl- and 4-(chlorobenzyl)-isoxazoles by freshly precipitated lead oxide, a reagent seldom used in organic chemistry. Other halides, ethers, and esters of the isoxazole series have been obtained from 3- and 4-halogenomethylisoxazoles, and 3-chloro-methylisoxazole has been reported in the Arbuzov rearrangement. Panizzi has used dichloromethylisoxazole derivatives to synthesize isoxazole-3- and isoxazole-5-aldehydes/ ... 

Isoxazole, 4-chloromethyl-3-ethyl-5-methyl-, 53, 71 Isoxazole, 3-ethyl-4-hydroxy-methy1-5-methyl-, 53, 70... 

Isoxazole, 3-chloro-5-hydroxymethyl-oxidation, 6, 27 Isoxazole, 4-chloromethyl-reactions, 6, 53 Isoxazole, 5-chloro-3-phenyl-reactions, 6, 58 Isoxazole, 3-cyano-reactions, 6, 30 Isoxazole, diacyl-synthesis, 6, 79 Isoxazole, 3,4-dialkyl-synthesis, 6, 83 Isoxazole, 3,5-dialkyl-synthesis, 6, 83 Isoxazole, 4,5-dialkyl-synthesis, 6, 83 Isoxazole, 3,5-diamino-2-amino-l-azirines from, 7, 89 Isoxazole, 3,5-diaryl-synthesis, 6, 63 Isoxazole, 2,5-dihydro-synthesis, 6, 79 Isoxazole, 4,5-dihydro-dehydrogenation, 6, 4... 

This procedure is illustrative of a general method for preparing a wide range of pure 3,5-disubstituted-4-isoxazole-carboxylic esters and (by hydrolysis) their acids,2 free from positional isomers. A wide range of both primary nitro compounds and of enamino esters can be used,2,3 and the esters thus obtained may then be used as reagents in the isoxazole annela-tion reaction.3,4 The only other general synthesis of these compounds involves chloromethylation and oxidation of a suitable 4-unsubstituted isoxazole.5 This procedure suffers from two difficulties low yields and the unavailability of starting isoxazole. Most methods of isoxazole formation yield a... 

The chloromethylation of isoxazoles (82) results in the formation of 4-chloromethyl derivatives (83), and their yield decreases in the following order 5-phenyl> 3,5-dimethyl> 5-methyl > 3-methyl >H (the parent isoxazole). 3,5-Dimethylisoxazole (53) also reacts with benzaldehyde in the presence of hydrogen chloride to give 4-(chlorobenzyl)isoxazole (84), and with formaldehyde in the presence of sulfuric acid it yields 4-hydroxymethylisoxazole (85). It is noteworthy that pyridine and its homologs, often compared with isoxazoles, do not undergo chloromethylation and hydroxymethylation (63AHC(2)365). 

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. 

PIPIDINES 3,5-Dimethyl-4-chloromethyl-isoxazole. Lithium aluminum hydride-Pyridine. 

Chloromethyl heterocycles react with silanes under Barbier conditions to yield the silylmethyl derivatives in good yields. 3,5-Dimethyl-4-(chloromethyl)isoxazole and 5-methyl-3-(chloromethyl)isoxazole couple with TMSCl-Mg in THF to yield the corresponding 4- and 3-trimethylsilylmethyl analogues in yields of 60 and 40%, respectively [138]. 

Ethyl-4-hydroxymethyl-5-methylisoxazole (54g., 0.38 mole) is dissolved in 70 ml. of methylene chloride and placed in a 500-ml. one-necked flask fitted with a 100-ml. pressmre-equal-izing addition funnel and a magnetic stirrer. The flask is placed in an ice bath and its contents are stirred while a solution of thionyl chloride (53 g., 32 ml., 0.45 mole) in 50 ml. of methylene chloride is added dropwise. Addition is complete in 1 hour, and the reaction is then allowed to warm to room temperature and stir for an additional hour. After retrieval of the magnetic stirring bar from the flask, the solvent is removed with a rotary evaporator and the dark residual liquid is distilled to yield 47-49 g. (78-81%) of 4-chloromethyl-3-ethyl-5-methyl-isoxazole, b.p. 77-78° (1.5 mm.) 1.4845 i.r. 1620, 680... 

The 4-(chloromethyl)isoxazole 13, which is readily accessible from 3,5-dimethyloxazole, serves as a C4-building-block in annulations to cycloalkanones (isoxazole annelation according to Stork). The primary step is alkylation leading to product 14, a masked triketone. On hydrogenation, the isoxazole ring is reductively opened and cyclization via the enaminone 15 leads to the enamine 16. On treatment with sodium hydroxide, this is converted into the bicycloenone 17 by hydrolysis, acid fission of the y dicarbonyl system and an intramolecular aldol condensation (analogous to a Robinson annu-lation) ... 

Chloromethyl)-3,5-dimethylisoxazole (32, readily accessible from acetylacetone) serves as a C4-building block in annulations to cyclanones, here cyclohexanone (Stork isoxazole annulation). 

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