Isoxazoles, hydrolysis

Isoxazole was first synthesized by Claisen in 1903 from propargylaldehyde diethyl acetal and hydroxylamine (03CB3664). It has also been obtained by addition of fulminic acid to acetylene in methanol-dilute sulfuric acid solution, by acidic hydrolysis of 5-acetoxyisoxazo-line, by reaction of /S-chloroacrolein or/3-alkoxyacrolein with hydroxylamine hydrochloride... 

The synthesis of pyrazoles and isoxazoles from l-heterobut-l-en-3-ynes is performed, as a rule, in an aqueous acid medium, i.e., under conditions favoring the hydrolysis and hydration of the initial enyne. This circumstance impedes rationalization of the experimental results. Therefore, it is reasonable to consider in brief the protonation and behavior of l-heterobut-l-en-3-ynes under the conditions of acid-catalyzed hydrolysis. 

Nucleophilic substitution of the halogen atom of halogenomethylisoxazoles proceeds readily this reaction does not differ essentially from that of benzyl halides. One should note the successful hydrolysis of 4-chloromethyl- and 4-(chlorobenzyl)-isoxazoles by freshly precipitated lead oxide, a reagent seldom used in organic chemistry. Other halides, ethers, and esters of the isoxazole series have been obtained from 3- and 4-halogenomethylisoxazoles, and 3-chloro-methylisoxazole has been reported in the Arbuzov rearrangement. Panizzi has used dichloromethylisoxazole derivatives to synthesize isoxazole-3- and isoxazole-5-aldehydes/ ... 

The only exception is represented by isoxazole-3-carboxylic acid in which the N—O bond is the only one to be broken, other bonds remaining unaffected hydrolysis of the intermediate (not isolated) gave carbethoxypyruvic acid. Quilico et al, reported the peculiar degradation of 3,3 -diisoxazolyl (124) ° treatment with sodium ethylate even at room temperature yields diacetyl with the evolution... 

Isoxazoles are stable toward many reagents yet undergo alkylation and hydrogenolysis readily. These features make isoxazoles, which may be considered masked diketones, a useful grouping in synthesis (22). Alkylation of 3,5-dimethyllsoxazole, followed by hydrogenolysis and hydrolysis, have been used to prepare a number of diketones (44) and tetraones (4i). Isoxazoles can be opened readily lo the amino ketone, a vinylogous amide (9). 

Hydrolysis of the isoxazole herbicide isoxaflutole rapidly produces a biologically active diketonitrile that is further degraded to products, which are partly bound to soil components and partly degraded to CO2 (Beltran et al. 2000 Lin et al. 2002 Taylor-Lovell et al. 2002) (Figure 1.24). 

The excitatoiy amino acids (EAA), glutamate and aspartate, are the principal excitatory neurotransmitters in the brain. They are released by neurons in several distinct anatomical pathways, such as corticofugal projections, but their distribution is practically ubiquitous in the central nervous system. There are both metabotropic and ionotropic EAA receptors. The metabotropic receptors bind glutamate and are labeled mGluRl to mGluRB. They are coupled via G-proteins to phosphoinositide hydrolysis, phospholipase D, and cAMP production. Ionotropic EAA receptors have been divided into three subtypes /V-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA), and kainate receptors (Nakanishi 1992). 

Addition of nucleophiles to the cyano group of cyanothiadiazole under basic conditions takes place with unusual ease <88AG(E)434,94ACS372). Hydrolysis to the amide, for example, can be effected at 0°C in the presence of a catalytic amount of sodium hydroxide or basic ion-exchange resin. At reflux temperature, hydrazine and monosubstituted hydrazines convert 3,4-dicyano-l,2,5-thia-diazole into the l,2,5-thiadiazole[3,4-. The base-catalyzed addition of acetone to cyanothiadiazole forms an enamino ketone, used as a key intermediate for the synthesis of a number of heterocyclic ring systems, e.g. isothiazole, isoxazole, pyrazole, pyrimidine, and thiazole <77H(6)1985>. 

Acid-catalyzed hydrolysis of the imidazo[4,5-f]isoxazole leads to the the two isoxazole monocyclic compounds, 40 and 41 (Equation 6), presumably via nucleophilic attack of water at the imidazole carbon atom <1999J(P1)817>. 

Hentriacontane-14,16-dione, a major component of wheat, barley and other plant waxes, has been synthesized from an isoxazole intermediate (78CC962). Heating 1-nitrohexadecane in benzene solution with pentadec-l-yne and phenyl isocyanate in the presence of a catalytic amount of triethylamine gave isoxazole (447) (35% yield). Hydrogenation of the purified, crystalline isoxazole over Raney nickel in ethanol followed by acid hydrolysis of the enamino ketone afforded the dione (448) in 75% overall yield (Scheme 100). 

This procedure is illustrative of a general method for preparing a wide range of pure 3,5-disubstituted-4-isoxazole-carboxylic esters and (by hydrolysis) their acids,2 free from positional isomers. A wide range of both primary nitro compounds and of enamino esters can be used,2,3 and the esters thus obtained may then be used as reagents in the isoxazole annela-tion reaction.3,4 The only other general synthesis of these compounds involves chloromethylation and oxidation of a suitable 4-unsubstituted isoxazole.5 This procedure suffers from two difficulties low yields and the unavailability of starting isoxazole. Most methods of isoxazole formation yield a... 

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. 

Touster and Carter hydrogenolyzed an isoxazole to a P-amino alcohol over Raney Ni.315 By hydrogenation of 3,5-diethoxycarbonyl-4-hydroxyisoxazole (105) over Raney Ni in ethanol at room temperature under high pressure, followed by hydrolysis, P,y-dihydroxyglutamic acid was obtained (eq. 13.167).315 The high activity of Raney Ni for the hydrogenolysis of fully substituted isoxazoles has also been noted by Stork et al.316... 

The kinetics of hydrolysis of energetic material precursors - mono- and dinitro derivatives of pyrazole, imidazole, 1,2,4-triazole, and isoxazole has been studied by the polarographic and photometric methods [647], The alkaline hydrolysis rate constants experimentally determined depend on the nature of the heterocycle. A possible mechanism for hydrolytic transformations of nitroazoles is proposed on the basis of the calculated thermodynamic parameters of the reaction. 

Another interesting example is the alkaline hydrolysis of the bi-isoxazolyl 50, which proceeds first by nucleophilic displacement of a nitro group giving 51 and then by fission to give 5-acetyl-3-nitroisoxazole (52).161 Examples of other reactions of nucleophiles with isoxazol-5(4//)-ones which also lead to... 

A formally similar rearrangement of isoxazol-5-ones probably proceeds by hydrolysis of the lactone linkage followed by recyclization.247... 

Dioximes of 1,3-diketones with acetylene gave pyrroles containing an 0-vinyl oxime 75 and 76 or an acyl substituent 77 and dipyrrole 78. With sterically hindered 1,3-dioximes, the main products were isoxazoles 79a, b and 80, formed due to hydrolysis of oxime function (Equation (21)) (05CHE722). 

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