Isoxazoles lithiation

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). 

Aminoisoxazoles 22 have been synthesized by nucleophilic addition of lithiated alkyl nitriles to a-chloroximes <06OL3679>. The cyclization of oxime dianions with diethyl oxalate afforded isoxazole-5-carboxylates 23 by acid-mediated dehydration of intermediate hydroxyisoxazolines <06S2515>. 

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). 

A regioselective method affording directly 3-phenyl-5-substituted isoxazoles 341, without isolation of isoxazoline intermediates, exploited reactions of NH2OH and a-benzotriazolyl-a,/3-unsaturated ketones 340, stereoselectively generated from benzotriazolylacetophenone and aldehydes in the presence of piperidine (Scheme 83) <2001JOC6787>. Treatment of /3-lithiated benzotriazolylvinyl ethyl ether with acid chlorides followed by cyclocondensation with hydroxylamine hydrochloride gave 4-benzotriazolyl-substituted isoxazoles <2005S245>. 

The nucleophilic addition of lithiated allyl phenyl sulfone to nitrones at 0 °C afforded 4-(phenylsulfonyl)isoxazol-idines as major products. The process probably involves the isomerization of the allylsulfonyl moiety of the initially formed hydroxylamine anion to vinylsulfone which then undergoes intramolecular Michael addition. For example, the chiral nitrone 536 afforded isoxazolidine 537 with high diastereoselectivity (Equation 88) <2005T3335>. When the same reaction was carried out in the presence of hexamethylphosphoramide (HMPA) at —80°C, the anti-a-sulfonyl homoallyl hydroxylamine was obtained. 

Lithiation of the methyl derivatives of such five-membered heteroaromatics as pyrrole , thiophene , l,3-thiazole ° , 1,3-oxazole , isoxazole , 1,3,4-thiadiazole , 1,3,4-oxadiazole and imidazole also occurs. For the sulfur heterocyclics, ring metallations and ring opening after lithiation are complications. 

Benzisoxazoles could be obtained by cyclization reactions forming N—O, O—C(7), or N—C(3) bonds as well as by heterocyclic rearrangements <84CHEC-I(6)l>. 1,2-Benzisoxazole (313) is synthesized from lithiated 3,5-dimethyl isoxazole (312) and a-oxoketene (311) (Equation (62)) <88TL50I>. Thermal transformations of ethyl nitrophenyl ethanoates (314) resulted in cyclization, to afford 2,1-benzisoxazole (316) via the ketene intermediate (315). Its mechanism has been discussed with evidence <95CC2457>. 

Synthesis and reactions of lithiated monocyclic azoles containing two or more hetero-atoms. Part 1 Isoxazoles , Iddon, B., Heterocycles, 1994, 37, 1263 Part III Pyrazoles , Grimmett, M. R. and Iddon, B., ibid., 1994, 37, 2087 Part V Isothiazoles and thiazoles , Iddon, B., ibid., 995,41, 533. Heinisch, G., Holzer, W. and Pock, S., J. Chem. Soc., Perkin Trans. 1, 1990, 1829. 

Reactions of Isoxazoles. The kinetics of the isoxazole azirine rearrangement (336) -> (337) and those of the isoxazole oxazole transformation (338) (339) have been determinedPalladium(II) chloride-triphenyl-phosphine catalyses the cross-coupling of 4-iodo-3,5-dimethylisoxazole with styrene to yield the trans- compound (340). 3,5-Dimethylisoxazole can be lithiated in two stages, first at the 5-methyl group and then at the 3-methyl group. Isoxazoles add hypochlorous acid to form 4-chloro-2,3-dihydro-... 

Oxazoles, imidazoles and thiazoles are lithiated in the 2-position, and pyrazoles and isothiazoles in the 5-position. With isoxazoles, w-butyllithium causes ring-opening. 

In view of the C-5-selectivity observed in lithiations, the selective 5-destannylation of a 4,5-di(tri- -butylstannyl)isoxazole is useful. This nice sequence utilised a coupling to a 2-iodonitrobenzene hydrogenation/hydrogenolysis caused ring cleavage of the isoxazole and produced an intermediate which cyclised with loss of water to give the indole. 

Exposure of ketone oximes which have an a-hydrogen, to two mol equivalents of butyllithium leads to C-lithiation syn to the oxygen reaction with dimethyl-formamide as electrophile then allows C-formylation and ring closure in situ to an isoxazole. " ... 

The fragmentation of lithiated isoxazoles 265 opens an access to lithium ynolates (Scheme 1-212). Lithiated 1,2,3-thiadiazoles 266 and 1,2,3-triazoles 267 provide lithium ynethiolates and yneamides by fragmentation (Scheme 1-212). 

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