2.1- Benzisoxazole-3-carboxylic acid

The intermediacy of an aci-nitro compound has been proposed for the sulfuric acid cyclization of o-nitrophenylacetic acid to yield a mixture of 2,1-benzisoxazole and 2,1-benzisoxazole-3-carboxylic acid. The acid does not decarboxylate under the reaction conditions. The proposed aci-nitro intermediate cyclized to an A/ -hydroxy compound which decomposed to the products (Scheme 179) (70JCS(C)2660). 

The electrochemical reduction of 3-nitrophthalic acid at controlled potentials gave 2,1-benzisoxazole-3-carboxylic acid. Cyclization is presumed to proceed via an intermediate oxime (67AHC(8)277). Treating 5-iodoanthranilic acid with acetic anhydride gave 3-acetoxy-5-iodo-2,l-benzisoxazole (596) (65JMC550). 

Benzisoxazole-3-carboxylic acid, 6-nitro-, reaction with methanolic hypochlorite, 59, 273... 

The model of the polymer derived from magnetic resonance and fluorescence spectroscopy studies has proved very useful in suggesting other types or reactions besides hydrolytic ones in which catalytic effects might be achieved. For example, it has been shown by Kemp and Paul46-47 that the decarboxylation of certain benzisoxazole carboxylic acids is very markedly accelerated in apolar, aprotic solvents, in contrast to water. Such an apolar solvent apparently lowers the energy of the charge-delocalized transition state in this decarboxylation reaction. Since... 

Isoxazoles, isoxazolines, isoxazolidines and benzisoxazoles are all thermally stable, distilling without decomposition, but the stability of the system depends on the substitution pattern. For example, aminoisoxazoles distill unchanged but the isoxazole carboxylic acids usually decompose at or above their melting points without giving the corresponding isoxazole. 

On the basis of UV studies, 1,2-benzisoxazoles are considered to be weaker bases than the above isoxazoles (8lAHC(29)l, p. 9) and the values for l,2-benzisoxazole-3-carboxylic acids are comparable with those of o -nitrobenzoic acids. 

Compound (122) is also obtained by decarboxylative ring-opening of l,2-benzisoxazole-3-carboxylic acid. It has also been concluded that the reaction involves an intermediateless, concerted loss of carbon dioxide via a transition state in which the negative charge is spread over the carboxyl group and the isox azole ring. 

Similar reactions have been observed with l,2-benzisoxazole-3-carboxylic acids (67AHC(8)277, p. 294) and the isomeric 2,l-benzisoxazole-3-carboxylic acids (67AHC(8)277, p.330). 

The structure was established on the basis of substitution at the 3-position (11CB2409), optical investigations (26LA(437)162), dipole moment (3.06 D) (44MI41600) and IR measurements (57MI41600, 66DIS(B)102). The first 2,1-benzisoxazole to be synthesized was 5,6-dimethoxy-2,l-benzisoxazole-4-carboxylic acid in 1881 (1881JPR353). 

Benzisoxazole-3-carboxylic acid decarboxylated ring opening, 6, 31 reactions, 6, 52... 

As with the isomers, 5-halogenation of 2,1-benzisoxazoles is favored, but this may be a consequence of an initially formed 4,5-addition product. Such an adduct has been isolated during chlorination [66T(S7)49 67AHC(8)277]. When 6-nitro-2,l-benzisoxazole-3-carboxylic acid (38)... 

A benzisoxazole moiety provides the nucleus of an anticonvulsant agent whose structure differs markedly from the traditional agents in this class. The synthesis starts with a compound (61-1) that incorporates a preformed benzisoxazole. Bromination proceeds on the position adjacent to the carboxylic acid (61-2). This intermediate loses carbon dioxide on heating, leaving behind the bromomethyl derivative (61-3). Displacement of the halogen with the ion from the reaction of imidazole with sodium hydride yields the alkylation product (61-4). The short side chain is then methylated by successive treatment with a base and methyl idodide to afford zoniclezole (61-5) [64]. 

The hydroxide ion induced rearrangement of Af-hydroxyisatin to 2,l-benzisoxazole-3-carboxylic acid has been described. A 14C label at the 3-position produced a 2,1-benzisoxazole with the label in the carboxyl carbon (Scheme 184) <66DIS(B)102). 

The l,3-dihydro-2,l-benzisoxazole-3-carboxylic acid was prepared by either base treatment of iV-hydroxyisatin or the rearrangement of N-hydroxyisatin monooxime with dilute acid (67AHC(8)277). The addition of amines to 3-unsubstituted-2,l-benzisoxazolium salts gave 3-amino-l,3-dihydro-2,l-benzisoxazoles (72CPB2209). 

This reaction was successfully used for the preparation of arylamides of 6-nitro-l,2-benzisoxazole-3-carboxylic acid (Scheme 2.62 and Table 2.2) [427, 428],... 

When Friedlander and Wleiigel1 in 1883 reacted the so-called anthranil (2,1-benzisoxazole) (2) with ethyl chloroformate, they obtained a compound (C8H5N03) which they called anthranilic carboxylic acid. A year later,... 

A second, related aspect of the medium effect is also likely to be important. Decarboxylation converts a polar, highly solvated -C02 group into a nonpolar, nearly unsolvated CO2. For the case of benzisoxazole-3-carboxylic acids, carboxyl desolvation has been demonstrated to be an important component of solvent catalysis of decarboxylation 113). Desolvation of the carboxyl group on binding to an enzyme may likewise be an important factor. Carbon isotope effects are consistent with this possibility (777). Oxygen isotope effects on formate dehydrogenase are also consistent with this mechanism 114). 

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