Anthranil N-oxides

In the case of the anthranil-N-oxides (181, X = CR, Y = 0), however, several examples of the isomeric o-nitrosobenzoyl compounds are known in the literature, viz., o-nitrosobenzaldehyde (182, X = CH, Y = 0),280,323 o-nitrosoacetophenone (182, X = CMe, Y = 0),133 and o-nitrosobenzophenone (182, X = CPh, Y = 0).156 They are described as almost colorless solids which give green solutions, and in this behave as typical nitroso compounds. The last-named compound (m.p. 129-130°) is clearly different from the 3-phenylanthranil-l-oxide316 described above, and it is the present authors opinion that only one can be correct. 

In light of the arguments put forward in the original review against the anthranil N-oxide structures,1 it is pertinent to mention that infrared and proton magnetic resonance spectroscopic data on o-nitrosobenzaldehyde indicate that it exists entirely as the nitrosoaldehyde and not in equilibrium with the isomeric anthranil N-oxide.247... 

Reductive removal of the Nj-oxide oxygen atom of the triazinium betaines (76) can be readily accomplished either by heating the betaine N-oxides in ethanol, or, more efficiently, by treatment with stannous chloride. Further reduction of the resultant betaines (77) with tin/hydrochloric acid results in ring cleavage and formation of arylhydrazides or anthranilic acid.87... 

Dicarbonylimidazole reacted with the anthranilic acid derivative (498) to produce the fused isoxazolone IV-oxide (499) (77ZOR462). Methyl nitroacetate reacted with indole-3-carbaldehyde to produce (500) (70KGS1505). Treatment of (501) with base gave 3,4,5-triphenyl-2-isoxazoline N-oxide (Scheme 142) (69JOC984). The reaction was reported to be a direct displacement as (502) did not give a product and no incorporation of deuterium was found using DOMe. 

Although the possibility of anthranil-A-oxide formation may be recognized, there are certain difficulties in the way of accepting at least one of the foregoing examples. The two generalized systems (181 and 182) differ, in certain conformations, only in their electron distribution, and interconversion would be expected to occur so readily as to preclude isolation of other than the energetically more stable form. Several examples may be cited to bear this out. Thus, 2-phenyl-benzotriazole-1-oxide (181, X = N, Y = NPh) is well-known,320 but no evidence for the independent existence of o-nitrosoazobenzene (182, X = N, Y=NPh) is available. The rapid tautomerism of benzofuroxan (181, X = N, Y = 0) from the 1- to the 3-oxide structure, through... 

Anthranil (119) and benzyne (from oxidation of 9 with lead tetraacetate) afford acridine (5%)81 depending on the sequence of bond forming and breaking, an oxygen-bridged cycloadduct and/or acridine N-oxide (120) may be intermediates in this reaction (Scheme 15), although 120 is known to react with benzyne in a different sense (Section IX). The addition of benzyne to oxazoles leads, ultimately, to anthracene derivatives in high overall yield.82b... 

Anthranils have been isolated from the reduction of benzodiazepine di-N-oxides with hydrogen sulfide and from the dilute sodium hydroxide-induced ring contraction of benzodiazepinone IV-oxides.200... 

Tolfenamic acid is used as an injectable formulation in cattle and swine. In rats and target animals, tolfenamic acid is metabolized by hydroxylation either of the methyl or the methylchlorophenyl group producing two metabolites further oxidation of the hydroxymethyl group to the corresponding aldehyde or carboxylic acid can produce two additional metabolites. The two hydroxylated metabolites of tolfenamic acid, N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid and N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid, are much less potent than the parent compound in terms of anti-inflammatory and analgesic... 

The most frequently reported oxidation reaction of isatins is the oxidation with alkaline hydrogen peroxide to give anthranilic acids. This procedure has been both as a proof of structure of isatins and as a method of synthesis of anthranilic acids. The oxidation has been applied to alkyl 8"10 11 23 33>38-40>46 49>50>118halo n.18.35.36-38-40.47.10 .11 . 119,136,240 alkoxy,26,a8 39,47,75.io7,ii8,i36 trifluoromethyl,33,38,137 and nitro8,120,217 isatins. Use of N-substituted isatins led to N-substituted anthranilic acids.66,71,125,158,169,243 In the oxidation of 5-bromo-l-(y-carbethoxypropyl)-7-ethylisatin, 60 was isolated after treatment with ethanol and acid.11 Oxidation of isatin derivatives 61 led, after treatment with diazomethane, to the acridine derivatives 62.67 Application of this oxidation method to 7-hydroxyisatins gave rise to benzoxazo-lones (63).2,41... 

Isatin (190) is a compound with interesting chemistry. It can be N- acetylated with acetic anhydride, N- methylated via its sodium or potassium salt and O- methylated via its silver salt. Oxidation of isatins with hydrogen peroxide in methanolic sodium methoxide yields methyl anthranilates (8lAG(E)882). In moist air, O-methylisatin (191) forms methylisatoid (192). Isatin forms normal carbonyl derivatives (193) with ketonic reagents such as hydroxylamine and phenylhydrazine and the reactive 3-carbonyl group also undergoes aldol condensation with active methylene compounds. Isatin forms a complex derivative, isamic acid (194), with ammonia (76JCS(pi)2004>. 

In practically all the instances of its use, attack of a double bond and of C-20 (between Nb and the C-21 to C-22 double bond) occurs. There is no instance of the simple oxidative disruption of a benzene nucleus indeed, the most vigorous conditions, aqueous alkaline permanganate at 50°-70°, lead to the oxidation of strychnine to N-oxalylanthranilic acid in about 8% yield. Brucine likewise gives 4,5-dimethoxy-iV-oxalyl-anthranilic acid, but in much lower yield (0.1 to 0.2%) (18). a-Colubrine (3-methoxystrychnine) gave a 2.7% yield of 4-methoxy- and /J-colubrine (2-methoxystrychnine) a 5.5% yield of 5-methoxy-iV-oxalylanthranilic acid (125). These oxidations fixed the positions of the methoxyl groups in the last three alkaloids. 

There are a few tetra- and pentacyclic analogues. Benzo analogues of 245 were prepared from pyridine-2,3-dicarboxylic acid anhydride and a tetralin derivative under conditions of the Friedel-Crafts reaction (85JCR(S)338). Pentacyclic compounds 258 (R = H or Me) were prepared from the bis adduct of anthranilic (or IV-methylanthranilic) acid to 1,4-benzoquinone, followed by cyclization in concentrated sulfuric acid (55JCS4440 66CB1991). 6-Methylquinoline-5,8-dione dimerized in the presence of ethanolic N-methyl-cyclohexylamine to 259 in very low yield and the dimerization is interpreted as two base-catalyzed addition reactions and three oxidation steps (71JCS(C)1253). 

Acetaldehyde, Acetamide, Acetaminophen, N-Acetyl Anthranillic Acid, Alumina (activated), Aluminum Chloride, Aluminum Oxide,... 

Laurent and Erdmann oxidized isatin, from which they obtained anthranilic acid (4). Carl Julius Fritzsche (also known as Iulii Federovich Fritsshe) in 1840 subjected anthranilic acid to alkaline distillation and obtained a powerful base, devoid of oxygen , that he called Anilin, from anil, the Portuguese word for indigo, which in turn had been derived from Arabic and Sanskrit. In 1842, the Russian chemist Nikolai N. Zinin reduced, with hydrogen sulfide, Nitrobenzid (nitrobenzene) to what was called Benzid (also Benzidam,... 

N-Substituted anthranilic acid derivatives are the starting materials of other preparations yielding IA. Heating of 13,46 14,47,48 or 15,28 or oxidizing 1628 gives various yields of I A. A 2-Isocyanatobenzoate (17), which is obtained either from phthalic anhydride and trimethylsilyl azide493 or from anthranilic acid silyl ester,498 is in equilibrium with N-trimethylsilyl-substi-tuted IA,49a,49b from which IA can be isolated by treatment with aqueous... 

The earliest example is the addition of benzyne (generated from 4 or by diazotization of anthranilic acid in situ) to N-phenyl sydnone (3-phenyl-l,2,3-oxadiazolium 5-oxide, 138)88 spontaneous loss of carbon dioxide from the intermediate adduct 139 gives 2-phenylindazole (140). Later workers have obtained 140 in higher yield (73%) and the corresponding 2,3-disubstituted indazoles from two other sydnones using benzyne generated by oxidation... 

Hydroxypyridine (201) itself possesses latent 1,3-dipolar character because of tautomerism involving 1-protiopyridinium 3-oxide (202). Aprotic diazotization of anthranilic acid in the presence of 201 gives two heterocyclic products [196 (20%) and 203 (23%)] which were isolated in separate experiments run under almost identical conditions.103,105 Formation of the bis-adduct 196 must involve cycloaddition of benzyne to 202 and N-phenylation and there is some evidence from related additions to 2//-phthalazin-1 -one (208) that the steps occur in this order.3 7b Formation of the isocoumarin structure 203 apparently involves electrophilic substitution of 201 by the benzyne precursor 5, followed by lactonization. From 3-hydroxy-6-methylpyridine compounds analogous to 196 and 203 were also obtained (10 and 29%, respectively). 3-Hydroxyquinoline afforded only the corresponding isocoumarin 204 (20%) whereas 4-hydroxyisoquinoline gave 4-phenoxyisoquinoline (12%) and the bis-adduct 205 (12%) with benzyne.103,105... 

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