Isoxazoles hydroxymethylation

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). 

Isoxazoles are presently known to undergo hydrogen exchange, nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, Vilsmeier-Haack formylation, and mercuration. The Friedel-Crafts reaction on the isoxazole nucleus has not yet been reported. 

Isoxazole, 3-chloro-5-hydroxymethyl-oxidation, 6, 27 Isoxazole, 4-chloromethyI-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... 

Further, isoxazole derivatives were subjected to two related reactions. 3,5-Dimethylisoxazole was found to react in the presence of dry hydrogen chloride with aromatic aldehydes (chlorobenzylation, 72- 71),and with formaldehyde in the presence of sulfuric acid it undergoes hydroxymethylation (72- 73). ... 

A highly modified methyl testosterone derivative also exhibits antiandrogenic activity. One synthesis of this compound involves initial alkylation of methyl testosterone (35) by means of strong base and methyl iodide to afford the 4,4-dimethyl derivative 6. Formylation with alkoxide and methyl formate leads to the 2-hydroxymethyl derivative 37. Reaction of this last with hydroxyl amine leads to formation of an isoxazole ring. There is then obtained azastene (38) . 

Reductive cleavage of the isoxazole ring within 182 installed the requested carbonyl and hydroxymethyl functionalities giving densely... 

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). 

Solid-supported nitrile oxides have the main advantage over those prepared in solution that formation of dimers is avoided. Thus, a 96-member library of 3-hydroxymethyl isoxazoles (265) [298] has been prepared from nitroethanol on a modified tetrahydropyranyl linker (263) as nitrile oxide precursor. The cycloaddition step was then performed by generating the nitrile oxide under the Mukaiyama conditions in the presence of alkynes (Scheme 59). As expected, the presence of dimer furoxane was never detected. 

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... 

Solid-phase synthesis of 3-hydroxymethyl isoxazoles 17 was accomplished in acceptable yields and purity through 1,3-DC of different alkynes 15 to resin bound nitrile oxides, generated from nitro compounds 14 under Mukaiyama conditions. This method is robust enough to be carried out by an automated synthesiser <01TL4951>. 

Bis(hydroxymethyl)propionic acid was also used to make the diether analog (Scheme IV). Treatment of the acid with methanol and boron trifluoride etherate gave the corresponding ester. The diol was then converted to the ether by alkylation with sodium hydride and methyl iodide. The dimethoxy ester was transformed to the isoxazole amine by reaction with the anion of acetonitrile (as in Scheme I) to yield the ketonitrile and then cyclization with hydroxylamine to give the isoxazole amine 17. Reaction with 2,6-dimethoxybenzoyl chloride gave the benzamide 18. 

Soluble PEG resin has been used in the synthesis of isoxazoles from polymer-bound aUtyne (Scheme 11.38). The alkyne was attached to the resin with an ester linkage, and the cycloaddition with nitrile oxides generated in situ gave resin-bound isoxazoles. Treatment with sodium hydroxide released the 5-hydroxymethyl-substituted isoxazoles from the resin in high yields and purities. 

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%. 

E. Cereda, A. Ezhaya, M. Quai, W. BarbagUa, Solid-phase synthesis of 3-hydroxymethyl isoxazoles via resin bound nitrile oxides. Tetrahedron Lett. 2001, 42, 4951-4953. 

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