Anthranils 2,1-Benzisoxazoles

Early workers favored a tricyclic structure (77) for the parent compound, but by analogy with the corresponding benzisoxazoles (anthranils)108 the o-quinonoid structure is now generally accepted, as in the conventional formula (2). This may not be quite the end of... 

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). 

Benzisoxazole (anthranil) is the less stable isomer of all the three and reacts at a considerably lower temperature range ( 800-1000K) at 1 ms reaction time. The quantum chemical calculations show that it has two isomerization channels. One leads to the production of l,3-cyclopentadiene-5-carbonitrile,l-aldehyde and the second channel to o-cyclo hexadienylidene ketene imine (CHKI). The two isomerization products are shown in Figure 6.37. 

Similar instability is found for 3-unsubstituted 2,1-benzisoxazole in the presence of base, ring opening to anthranilic acid derivatives occurring readily (see Section 4.16.3.1.6). 

In contrast to the 3-amino derivatives, 3-hydroxy-2,l-benzisoxazoles are relatively labile. With nitrous acid they undergo ring fission to anthranilic add. Its 3-acetoxy derivative (258) reacts with primary amines to form the quinazolone (259) (67AHC(8)277, p. 297). 

Benzisoxazoles, also called anthranils as derivatives of anthranilic acid, are most commonly formed by the closure of bonds C(l)—C(2) or C(2)—C(3), or the introduction of atom C(3) resulting in formation of bonds C(2)—C(3) and C(3)—C(3a). As with the 1,2-benzisoxazole series, many early structural ambiguities were present in assignments (67AHC(8)277, 62HC(17)1, 66Dis(B)102). The 3-hydroxy compound is primarily in the keto form and only recently have ethers been reported. 

A high yielding synthesis of anthranil from 2-nitrobenZaldehyde makes use of zinc and allyl bromide as the reducing agent. The method has also been used for the preparation of 3-substituted anthranils from 2-nitrophenyl ketones <99H(51)1921>. A solid phase synthesis of 3-aminobenzisoxazoles 15 is based on the displacement of fluoride from 2-fluorobenzonitriles by the Kaiser oxime resin and subsequent hydrolysis of the C=N bond <99JOC4547>. A synthesis of 3-(2-dialkylaminoethyl)benzisoxazoles from oximes of 2-hydroxyphenyl ketones has also been described <99H(51)2139>. ... 

Each ring system is known in the literature by several names. Thus, 1 is described asindoxazene, 1,2-, 4,5-, or a,j8-benzisoxazole, benz[d]is-oxazole, or simply benzisoxazole, while for 2 the names anthranil, anthroxan, 2,1-, 3,4-, and j8y-benzisoxazole, benz[c]isoxazole, and benzpseudoxazole can be found. The preferred nomenclature of Chemical Abstracts and the Ring Index is 1,2-benzisoxazole for 1 and... 

Isoxazole (CA) 1,2-BenzisoxazoIe (CA) 2,1-Benzisoxazole (CA) 1,2-Oxazole Indoxazene Anthranil... 

Thermochemical experiments were performed to determine the standard molar enthalpy of formation of anthranil in the gaseous phase. A comparison of this value with that obtained from quantum-chemical calculations for 1,2-benzisoxazole showed that anthranil 1 is significantly less stable (A//°f= 180.8 2.1 kjmol ) than its isomer 2 (A//°f= 138.9 3.1 kJmoP ). This difference of about 42kJmol , even if significant, suggests that by thermochemical criteria, if aromatic character is ascribed to 1,2-benzisoxazole, a significant aromatic character must also be associated with anthranil <2004EJ03340>. 

Aminoisoxazoles were obtained from (Z)-3-alkyl-3-nitro-2-phenylpropenenitriles using baker s yeast <1996SL695>. Reductive cyclizations of 2-nitroacylarenes allowed the synthesis of anthranil derivatives. For example, a series of 5-substituted 2,1-benzisoxazoles where prepared by reduction with SnCl, and subsequent... 

The nomenclature of benzfused or of any fused system or spiral system follows the Hantszch-Widman system of nomenclature. In these fused systems, the first ring or benzene ring is the base component of the second ring system, isoxazole. Thus the complete name becomes benzisoxazole. The bonds in the base component are labeled as a, b, c, d, e, etc. Atoms in the hetero-ring component are numbered as 1-7 as shown in (2) and (3). Two classes of benzfused systems, that is, 1,2-benzisoxazole (or indoxazene) (2) and 2,1-benzisoxazole (or anthranil) (3) exist. 

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,... 

Isoxazole (1), 2-isoxazoline (2), isoxazolidine (3), 1,2-benzisoxazole (4) (sometimes termed indoxazene) and 2,1-benzisoxazole (5) (often referred to as anthranil) are numbered as shown. The chemistry of isoxazoles (79AHQ25)147, 63AHC(2)365, 62HC(17)1>, isoxazolines <62HC(17)l,p.95), isoxazolidines (77AHC(21)207, 62HC(17)l,p. 229> and benzisoxazoles... 

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