1.2- Benzisoxazole ring synthesis

Ring Synthesis of IR-Indazoles, 1,2-Benzisothiazoles and 1,2-Benzisoxazoles The earliest syntheses of 1,2-benzisoxazoles depended on the cycUsation of an ortfto-haloary 1-ketone oxime, typical conditions are shown below and involve an intramolecnlar nncleophilic substitution of the halide. Only one geometrical isomer of the oxime will ring close. Applying this approach to amidoximes is easier, because the two imine geometrical isomers in such compounds are easily interconvertible. Comparable reaction with hydrazones produces indazoles. ... 

This strategy allowed a little later the group of Hilvert/ thanks to the synthesis of a hapten 18 carrying an amidinium function, to generate antibodies that are able to very effectively accelerate the ring opening reaction of a benzisoxazole cycle (4at/ uncat= 3 x 10 ) (Figure 14(b)). 

It has also been fotind recently that the 3-(/>-tolyl)- and 3-phenyl-6-methyl-1,2-benzisoxazoles (90 and 91) can be utilized in the Anil Synthesis,54 since this ring system was found to be alkali stable. Hence, for example, 90 and 91 give, on reaction with Schiff s base from 1-formyl-naphthalene and p-chloroaniline, the styryl derivatives 92 and 93, respectively. 

The 2,1 -benzisoxazole (anthranil) ring system is of interest as a key intermediate for the synthesis of other heterocycles. 2,1-Benzisoxazoles can be derived from the direct multistep domino reaction of some carbanions with nitroarenes or by conversion of the products of nucleophilic substitution of hydrogen in nitroarenes. As early as in 1960, Davis and Pizzini reported that the reaction of 4-chloronitrobenzene with phenylacetonitrile in the presence of potassium hydroxide in protic media affords 3-phenyl-5-chloro-2,l-benzisoxazole in high yield [80] (Scheme 17). 

Beier and Pastyrikova (13MI411) reported that reductive ring opening of SFs-substituted benzisoxazoles 78a, 79a using iron in aqueous AcOH resulted in excellent yields of ori/ o-aminobenzophenones 100, 101, which can be used as precursors for the synthesis of other SFs-substituted heterocycles such as quinazoHnes (see Section 2.8), as weU as for the synthesis of SFs-substituted quinolines. Thus 6-SFs-quinoline 102 was prepared in high yield by the Friedlander annulation reaction of 101 with excess ethyl acetoacetate in the presence of catalytic cerium (IV) ammonium nitrate (CAN). Similarly, aminoketone 100 was condensed in good yield with cyclohexanone to provide 7-SFs-quinoline 103 (Scheme 25). 

Review articles have featured advances in the cycloisomerization of l,n-allenynes and Rn-allenenes, " reactions for synthesis of quaternary centres bearing a nitrogen substituent, " the Ramberg-Backlund reaction transforming a-halosulfones into alkenes, " and ring expansion of l,2-benzisoxazol-3-ones with a Vilsmeier reagent system, POCI3 and dimethylformamide (Scheme 75). " ... 

Benzisoxazoles.—The reaction of salicylaldehyde oxime with thionyl chloride in pyridine to yield 1,2-benzisoxazole (539 R = H) constitutes a new synthesis of this ring system.Thermolysis of the azido-ketone (540) affords the linearly annelated anthranil (541). ° The benzisoxazoles (539 R = H, Me, or Ph) rearrange photochemically to the benzoxazoles (543) via intermediate azirines (542). ° Irradiation of an aqueous solution of the benzisoxazolium salt (544) gives the phenolic ketone (545). ° ... 

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