4- Halo-isoxazoles

The behaviour of /S-oxovinylazides is quite similar to those above. The Z isomer (556), formed from the /S-halo carbonyl compound and sodium azide, is unstable losing N2 and forming the isoxazole (557) in an anchimerically assisted concerted reaction (75AG(E)775, 78H(9)1207). At moderate temperatures (50-80 °C) the E isomer formed acylazirines which at higher temperatures rearranged to oxazoles and isoxazoles. 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a-halo- 8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

KOHLER Isoxazole-N-oxide Synthesis Synthesis of Z-isoxazole-Z-oxides from 1,3-dinitroal(anes or l-halo-3 nltro aikanes. 

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. ... 

Several specialized cyclization strategies should not be dismissed. A novel rhodium acetate-mediated cyclization was employed for the first synthesis of 3-methyl-4,6-diphenylfuro[3,4-tf]is-oxazole (9) from the 5-(a-diazobenzyl)isoxazole (185) (Equation (56)). The reactive intermediate is believed to be a carbenoid species <9iCB248i>. Another strategy exploits the reactivity of 4-halo-pyrazol-5-ones (e.g., 186) with stabilized anions (e.g., cyanoacetate esters and nitriles) to afford the 4-cyanofuro[2,3-c]pyrazol-5-ones (187) and 5-aminofuro[2,3-c]pyrazoles (188) (Scheme 30) <84H(22)2523>. Also of interest is the trichloroacetonitrile cyclization of aminopyrazole ketones (189) to the pyrrolo[2,3-c]pyrazoles (190) (Equation (57)) <86S74>. The generality of this cyclization is not known. 

Reaction of a 1,3-diketone with hydroxylamine gives an isoxazole 50 via the isolable monoxime 48 and 5-hydroxydihydroisoxazole 49 (Scheme 34). Various modifications of this procedure involving other 1,3-dielectrophiles are known the examples can be represented by the reaction of alkynyl ketone 51 with hydroxylamine hydrochloride leading to the 3-substituted isoxazole 52 (Scheme 35) <2000J(P1)2311 >, and the electrophilic cyclization of O-methyl oximes 53 allowing access to a variety of 3,5-disubstituted-4-halo- or -4-selenoisoxazoles 54 under mild reaction conditions (Scheme 36) <20050L5203>. 

KOHLER Isoxazole-N xideSynthesis Synthe s of a-isoxazote-Z-oxIdes from 1.3-dinitroakanes or 1-halo-3-fl ro alkanes. 

Other synthetic approaches involve cyclocondensations of hydroxylamine with 1,3-bielectrophiles. For instance, starting from conjugated alkynyl-carbonyl compounds 14, electrophilic cyclization allowed a facile access to a variety of 3,5-disubstituted-4-halo(or seleno)isoxazoles 16 in high yields under mild reaction conditions, by treatment of 0-methyl oximes 15 with ICl, I2, Br2, or PhSeBr <050L5203>. 

Isoxazoles are quatemized by iodoalkanes or dialkyl sulfates. Electrophilic substitutions such as halo-genation, nitration, sulfonation, Vilsmeier-Haack formylation and acetoxymercuration, occur at the 4-position, provided this position is unsubstituted. As with oxazole, the pyridine-like N-atom impedes electrophilic substitution, so that isoxazoles are less reactive than furans but more reactive than benzene. 

Highly regioselective tandem syntheses of 3-halo-5-substituted isoxazoles 3 have been developed from l-copper(I)-alkynes and dihaloformaldoximes under base-free conditions. This methodology inhibits the formation of halonitrile oxides precluding 1,3-dipolar cycloadditions (1,3-DC) (14OL6140). 

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