Anthranils, 3-aryl-, reaction with

Chlorooxadiazoles (82) react with amino compounds R NH2 (R = NH2, NHPh, alkyl, or aryl), secondary amines R R NH and azide ion to give products of nucleophilic displacement (76e), (76b), and (54i) respectively <84Mi 406-03, 90AP(323)595>. Reaction with anthranilic acid resulted in nucleophilic displacement with subsequent cyclization to oxadiazoloquinazolone (83) <84JIC436>. 

Alkyl- and aryl-substituted carboxylic acid derivatives such as ethyl 4-methoxybenzoate, diethyl phthalate,104 aryl- and alkylcarboxylic add halides or anhydrides10,2 5 8 give benzoxazinones (193). When IA was brominated in glacial acetic acid, 193 (R2 = CHBr2) was obtained.259 Anthranilic acid (4) with A-methyl IA (24) leads to 194, which cyclizes in sulfuric acid to the benzoxazinone 195134 (Scheme 33). Reaction of /V-formylanthranilic acid (196) (available from 1A and formic acid) with IA again yields the quina-zolinone 19710 260 (Eq. 19). 

The developed solid-phase approach started with the preparation of immobilised ureas 114 obtained via acylation of amino acids linked to acid-labile Sasrin resin 104 with ortho-methoxycarbonyl aryl isocyanates or activated para-nitrophenyl carbamates 113. Alternatively, ureas of type 114 could also be generated by reaction of anthranilic esters 115 with immobilised amino acid-derived isocyanates (easily generated from tethered amino acids with triphosgene or phosgene in toluene in excess of a base such as 2,6-lutidine) or activated carbamates 116 (Scheme 4.1.23). 

Based on the high levels of activity obtained for DIO, a series of N-pyridyl analogs were explored. We also wished to study the effect of substituents R4 on the aryl portion of the anthranilic diamide. Figures 4-6 illustrate the routes by which these compounds were prepared [2]. The method presented in Figure 4 was used to prepare the 3-trifluoromethyl-5-pyrazolecarboxylic acid 26. This method involves regioselective lithiation of 3-trifluoromethylpyrazole 25 followed by reaction with carbon dioxide, to afford the pyrazole carboxylic acid 26 in good yield. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

It was found inadvisable to use more than four molecules of form-amide [ (47) when R = H] per molecule of anthranilic acid and the condensation produces best results when the mixture is heated at 120 -130°C for 2 hr followed by further heating at 170°-180 C for 2 hr. Other variants of this reaction involve the use of ammonium o-acylaminobenzoates, anthranilic acid in the presence of nitriles and acetic anhydride, o-acetamidonitrile with acetic anhydride or hydrogen peroxide, anthranilic esters and aliphatic or aromatic amides or amidines, isatoic anhydride with amides or amidines, and anthranilic esters with aryl iminochlorides in acetoned The mechanism proposed by Bogert and Gotthelf has had experimental supporR and is represented in Scheme 12. 

Substituted phenacyl anthranilates were prepared by reaction of sodium anthranilate with substituted phenacyl halides in DMF. The phenacyl esters were cyclized in polyphosphoric add or by heating to give the respective substituted 2-aryl-3-hydroxyquinoline-4(l. -ones in high yield <95CCC(60)1357>. 

Hydrolysis of 3-alkyl-l,2,3-benzotriazin-4(3i/)-ones (10, R = alkyl) with cold, aqueous potassium hydroxide leads to anthranilic acid derivatives. The related 3-aryl-l,2,3-benzotriazin-4(3H)-ones (10, R = aryl) react less readily, but on treatment with hot aqueous or alcoholic potassium hydroxide are converted into 3-aryltriazenes (53, R = aryl) which, on further reaction, give anthranilic acids. ... 

Hot, dilute sulfuric acid hydrolysis of 10, R = alkyl, aryl initially gives anthranilic acid, which is converted into salicylic acid on prolonged reaction. When dilute hydrochloric acid is employed with the same substrates iV-alkyl- and AT-arylsalicylamides are formed, but concentrated hydrochloric acid results in the formation of o-chlorobenzoic acid. - ... 

In a follow-up communication,26 similar chemistry was used for the production of 2-substituted benzofurans beginning not with an anthranilic acid derivative, but with a resin-bound ortho-hydroxy aryl iodide 3. In the solid-phase work, depicted in Scheme 5, the relevant carboxylic acid was linked to TentaGel via a Mitsunobu reaction, and after deprotection was seen to undergo smooth Heck coupling and cyclization, giving essentially pure compounds in 40-70% overall yield after cleavage. 

Reaction between an iV-alkyl or JV-aryl substituted anthranilic acid (94) and phosphorus pentasulfide, in refluxing xylene, alfords a mixture of a 2,l-benzisothiazoline-3-thione (95) and a 4-3,3 -bis-2,1-benzisothiazoline (96).123,124 Oxidation of the thione (95) with... 

Deveaux et al. [21] reported that mefenamic acid, being an N-aryl derivative of anthranilic acid, can be characterized by two color reactions. The color reactions, negative with N-aryl derivatives of aminonicotinic acid, are associated with the diphenylamine structure. For the first color reaction, add to a test tube approximately 0.5 g of oxalic acid dihydrate and at least 1 mg of the test material. Place the tube into an oil bath at 180-200°C for 4-5 min. After cooling, dissolve the residue in 10 mL of 95% ethanol to obtain a stable, intense blue solution (absorption maximum at 586-590 nm). To use the reaction for capsule formulations, extract the active ingredient with acetone and filter prior to the assay. For the second color reaction, add mefenamic acid (100-800 pg) in 1 mL of H0Ac-H2S04 (98 2, v/v), 5 mL of HOAc-HCl (50 50, v/v) and 1 mL of 0.10% (w/w) aqueous levulose. Heat the mixture for 25 min at 100°C, and after cooling, measure the absorbance at 597 nm. 

A study of the effect of the structure and size of the amine radical (butylamine, dibutylamine, hexylamine, piperidine, aniline) on its reactivity in the nucleophilic replacement of tosyloxy groups in cellulose tosylate has shown (29) that this reactivity depends primarily on the basicity of the amine. TTiis assumption was confirmed by a study of the interaction of cellulose toxylates of different degrees of substitution (DS from 0.3-1.7) wit iminodiacetic and anthranilic acids 30, 31). TTie degree of substitution of the reaction products with respect to the N-carboxyalkyl(aryl)amino groups was found to be lower than that of the corresponding N-alkyl(aryl)araino derivatives. 

JCS(P1)659). For condensation products with other aldehydes, a linear pentacyclic structure was proposed, but not proved (1894JCS76). 2-Chloro-or 2,5-dichloro-l,4-benzoquinones are arylated with diazotized anthranilic acid the reaction is postulated to proceed via a pentacyclic quinone 376, which was isolated in low yield (59JCS3250). 

Condensation of anthranilic acid with various ort/zo-esters and reaction of semicarbazides, gave 2-substituted benzoxazin-4-ones and also by the reaction of hydrazones with aryl-/alkyl-ureas and by salicylaldehyde or 2-hydroxyacetophenones with 4-aryl-/alkyl-semicarbazides. Hydrolysis of o-aminoesters and subsequent treatment with phosgene gave 40. Fused oxazine with bridge head nitrogen 41 and triazolo[3,4-Z>]thiazines 42 were also prepared . The 2,3-dihydrobenzoxazine 43, thiomorpholines 44 and phenothiazines 45 were prepared. ... 

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