Metalation isoxazoles

Despite the weak basicity of isoxazoles, complexes of the parent methyl and phenyl derivatives with numerous metal ions such as copper, zinc, cobalt, etc. have been described (79AHC(25) 147). Many transition metal cations form complexes with Imidazoles the coordination number is four to six (70AHC(12)103). The chemistry of pyrazole complexes has been especially well studied and coordination compounds are known with thlazoles and 1,2,4-triazoles. Tetrazole anions also form good ligands for heavy metals (77AHC(21)323). 

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>. 

Neutral azoles are readily C-lithiated by K-butyllithium provided they do not contain a free NH group (Table 6). Derivatives with two heteroatoms in the 1,3-orientation undergo lithiation preferentially at the 2-position other compounds are lithiated at the 5-position. Attempted metallation of isoxazoles usually causes ring opening via proton loss at the 3-or 5-position (Section 4.02.2.1.7.5) however, if both of these positions are substituted, normal lithiation occurs at the 4-position (Scheme 21). 

Although isoxazoles are comparatively weak electron donors, complexes with numerous metal ions, notable metal(II) ions, have been reported. The ligands include isoxazole and its methyl, phenyl, amino and hydroxy derivatives. They are listed with references in Table 5. 

The mechanisms of the electrophilic substitutions in the isoxazole nucleus have not yet been studied. They should not differ fundamentally from those usually accepted for the substitution of aromatic systems but the structural specificity of the isoxazole ring might give rise to some peculiarities, as recently specially discussed.One important point is that isoxazole shows a clearcut tendency to form coordination compounds. Just as pyridine and other azoles, isoxazoles coordinate with halogens and the salts of heavy metals, for example of cadmium,mercury,zinc. Such coordination... 

The degradation which occurs on reduction with the alkali metals involve a mechanism that is considered to be firmly established and in the isoxazole series appears to proceed according to the usual scheme,... 

Enantiomerically pure 4.5-dihydro-3-[(/J)-(4-methylphenylsulfinyl)methyl]isoxazoles 16 arc readily available from the reaction of metalated 4,5-dihydro-3-methylisoxazoles 14 with (-)-menthyl (5)-4-methylbenzenesulfinate (15), under inversion of the configuration at sulfur, followed by separation of the resulting diastereoiners27-28. 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

It is fairly stable as an ethereal solution, but the isolated acid is explosively unstable, and sensitive to heat, shock or friction [1], In a new method of preparation of the acid or its salts, pyrolysis of 4-oximato-3-substituted-isoxazol-5(4//)-ones or their metal salts must be conducted with extreme care under high vacuum to prevent explosive decomposition [2],... 

Isoxazoles are privileged aromatic heterocycles due to their wide spectrum of biological activities and their use as versatile building blocks in organic synthesis. Recent progress in the field of transition-metal-catalyzed cross-coupling reactions on isoxazole systems has been summarized and discussed <06EJO3283>. 

Isoxazoles and benzisoxazoles that are unsubstituted at the 3-position readily undergo the base-reduced ring fragmentation shown above, and there are therefore no reports on the successful metalation of these types of compound. 3-substituted isoxazoles do undergo lithiation, at the 5-position, but ring fragmentation rapidly follows, even at -60°C in the case... 

When both the 3- and the 5-positions of isoxazole are substituted, stable metalated derivatives can be obtained via direct lithiation at C-4, with subsequent reaction giving rise to a variety of 3,4,5-trisubstituted in very good yields (Scheme 71) (70CJC1371). 

Depending on the substitution pattern and reaction conditions, 3-alkyl-4,5-dihydroisoxazoles aremetalated either at the 3a(exo)-position or at the C4(endo)-position18. Thus, metalation and alkylation of 4,5-dihydro-3-methyl-5-pheny]isoxazole (4) leads to both regioisomeric products, whereas endo deprotonation is more favorable in the case of the 3-ethyl derivative18. 

Flash thermolysis of 4-substituted isoxazol-5(4//)-ones can be used to generate alkynes, isocyanides, aminoisocyanides and ketenimines (77C258, 76HCA2615). Decomposition of the oxime (538) at an oven temperature of 450 °C produces C02, benzonitrile and fulminic acid (539 equation 5) (79AG(E)467). This method thus offers a safe alternative to the synthesis of fulminic acid from the explosive metal fulminates. 

Methyl-4,6-diphenylfuro[3,4-d]isoxazole 81 is available from 80 by a metal-catalyzed nitrogen extrusion (mp 128°C 91CB2481).The synthesis of other stable derivatives (82a-e) has also been reported (96H1165). The crystal structure of 82b was determined (96H1165). 

In an approach of the type employed by Stevens, the metal-free corrin nucleus can be constructed, as shown in Scheme 26, by stepwise progression in either a clockwise or an anti-clockwise manner depending upon the choice, the tris-isoxazoles (294) or (295) should be accessible. 

S-Diketones.1 /3-Diketones react readily with hydroxylamine to form isoxazoles and can be reformed by acid hydrolysis and thus can function as / -diketone synthons. For example, 3,5-dimethylisoxazole, readily obtained from acetylacetone, can be metallated by a variety of bases, and the anion so obtained can be alkylated at the C5-methyl group. A second alkylation occurs only at the C3-methyl group. Thus it is possible to prepare selectively 3,5-dialkylisoxazoles, from which the corresponding / -diketones are obtained in 70-95% yield by acid hydrolysis in ethanol. 

The tetrahydro-derivatives of the oxazole and isoxazole system are unstable. As a consequence, only acyclic products have been reported from the reductions with complex metal hydrides. 2,5-Diphenyl-oxazole (119) gave 2-benzylamino-l-phenylethanol (120),141 and 3,5-diphenyl-2-isoxazoline (121) was converted to 3-amino-l,3-diphenylpropanol (122)142 on reduction with lithium aluminum hydride. 3-Phenylbenzisoxazole was resistant to reduction with lithium aluminum hydride and sodium borohydride,143 but benz-oxazole (123), benzoxazol-2-one (124), and benzoxazol-2-thione (125) have been reported 141 to yield 2-methylaminophenol (126) on reduction with lithium aluminum hydride. 

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