Reduction of isoxazoles

The reduction of isoxazoles is often rather peculiar and its course depends on the nature both of the isoxazole and of the reducing agent. Together with a normal reduction of groupings in the side chain, cleavage of the nitrogen-oxygen bond of the heterocyclic nucleus often occurs. 

Acylaminoenaminoketones (113) are readily accessible by reduction of isoxazoles in the presence of bases they give imidazoles (114) in a facile... 

Other reagents recommended for the reduction of isoxazoles to 1,3-enaminoketones include samarium diiodide, molybdenum hexacarbonyl in aqueous acetonitrile, and diiron nonacarbonyl in water. Electrochemical methods have also been employed." A particularly mild method involves reaction with the reduced form of the coenzyme lipoamide (LA2) complexed with iron(II). Birch reduction (sodium and... 

Oxygen-containing azoles are readily reduced, usually with ring scission. Only acyclic products have been reported from the reductions with complex metal hydrides of oxazoles (e.g. 209 210), isoxazoles (e.g. 211 212), benzoxazoles (e.g. 213 214) and benzoxazolinones (e.g. 215, 216->214). Reductions of 1,2,4-oxadiazoles always involve ring scission. Lithium aluminum hydride breaks the C—O bond in the ring Scheme 19) 76AHC(20)65>. 

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. 

SnCl2 reduction produced the 4-hydrazinoisoxazole (243). In ethanol the diazonium salt reacted with the 4-aminoisoxazole to produce the linear triazine (244) (Scheme 85). Diazoisoxazoles can also be treated with KI or H20/urea to produce the 4-iodo or 4-hydroxy derivatives (63AHC(2)365). These Sandmeyer reactions have been extended to a variety of isoxazole systems (77JMC934, 63AHC(2)365). 

Oxidation and reduction can initiate changes leading to heterocycle-heterocycle conversions. The reaction of tetraphenylfuran with singlet oxygen (Scheme 34) (B-73MI50303) and that of isoxazoles with LAH (Scheme 35) are examples. 

C. Reductive Cleavage of Isoxazoles and of Their Hydrogenated Derivatives... 

Syntheses of Carbocyclic Compounds (1.V.2.V )-2 (.V )-Amino(4-metho-xyphenyl)methyl]cyclopropan-l-ol 392 (Scheme 1.45) has been prepared by a stepwise procedure involving a 1,3-dipolar nitrile oxide cycloaddition to allyl alcohol followed by a constmction of the cyclopropa d isoxazole system, and reduction of the bicycle (436). 

The synthesis of new 11-deoxyprostaglandin analogs with a cyclopentane fragment in the oo-chain, prostanoid 418, has been accomplished by a reaction sequence involving nitrile oxide generation from the nitromethyl derivative of 2-(oo-carbomethoxyhexyl)-2-cyclopenten-l-one, its 1,3-cycloaddition to cyclopenten-l-one and reductive transformations of these cycloadducts (459). Diastereoisomers of a new prostanoid precursor 419 with a 4,5,6,6a-tetrahydro-3aH-cyclopent[d isoxazole fragment in the oo-chain have been synthesized. Reduction of 419 gives novel 11-deoxyprostanoids with modified a- and oo-chains (460). 

Coupling comparable with that found in awft -oximes is also observed in cyclic systems such as pyridine, quinoline, 5-phenylisothiazole and isoxazole in which the nitrogen lone-pair lies E(cis) to the adjacent hydrogen. Confirmation of the importance of the lone-pair orientation is further derived from the fact that removal of the nitrogen lone-pair by protonation or quatenization results in the reduction of H) to the value found in... 

Imidazo[4,5-r-]isoxazole 39 <1999J(P1)817>, first prepared by Tennant et al., undergoes reduction of the N-O bond under classical hydrogenation conditions, to yield the substituted imidazole 43 in excellent yield (Equation 7). 

Four-membered rings are not obtained during reduction of a-nitro-/ -keto alkenes the oxygen of the hydroxylamine intermediate attacks the electrophilic center1,71 with formation of isoxazole derivatives. 

Hydrogenation of isoxazole 189 over Raney nickel afforded the 7-amine 191a, probably via the intermediate 190. In addition, reduction of the isomeric isoxazole 192 effected formation of the pyridone 191b.159... 

Isoxazoles have been used to transpose functionality within a,/3-unsaturated carbonyl compounds (72JA9128). Thus, on exposing either (E)- or (Z)-/3-ionone oxime (449) to a mixture of iodine-potassium iodide in hot aqueous THF containing sodium bicarbonate, the isoxazole (450) was formed in high yield. Catalytic reduction of this isoxazole led... 

Reductive cleavage of isoxazoles.2 Isoxazoles (1) are reductively cleaved to p-amino-a,p-unsaturated aldehydes or ketones when refluxed in moist acetonitrile containing Mo(CO)6 (0.2-1.0 equiv.). 

Reductive cleavage of isoxazoles. In the presence of Mo(CO)6 and water (1 equiv.), isoxazoles are cleaved to / -amino-a,/ -enones in good yield.1... 

Reductive cleavage of isoxazoles.2 Sml2 (2 equiv.) in the presence of CH3OH as a proton source is an efficient reagent for reductive cleavage of the O—N bond in isoxazoles. 

Dipolar cycloaddition of nitrile oxides to olefins and acetylenes is among the most widely exploited synthetic routes towards isoxazoles and isoxazolines. It is well-known that microwave irradiation in cycloaddition reactions considerably reduces reaction times. Indeed, the use of dielectric heating (microwave-heated reactions were performed in a flask with a reflux condenser mounted outside the apparatus) allowed for a remarkable reduction of the cycloaddition reaction time from 6-12 hours to merely 3 minutes [69]. Simple aqueous workup provided the target isoxazoles and isoxazolines. The requisite nitrile oxides for the cycloaddition reaction were generated in situ from the corresponding nitroalkanes, 4-(4,6-dimethoxy [1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 4-dimethylaminopyridine (DMAP) (Scheme 22). 

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