Anthranilic acid formation

The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

Esterification. The formation of an ester from an acid (or its derivative) and an alcohol is of limited appHcation siace carboxyUc esters are comparatively rare substitueats ia dyes. Esters of A/-(3-hydroxyethylaniLiaes are important iatermediates for azo disperse dyes for polyester. Another example is methyl anthranilate, formed by the classical esterification of anthranilic acid usiag methanol and sulfuric acid. 

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. 

The carcinogenic properties of tricycloquinazoline (60) were studied in detail because of its possible formation from anthranilic acid derivatives in nature. It possessed stronger carcinogenic activity toward mice (72%) than rats (27%). Its action resembled that of embedded plastic materials, because it was recovered unmetabolized. ... 

Cain RB (1968) Anthranilic acid metabolism by microorganisms. Formation of 5-hydroxyanthranilate as an intermediate in anthranilate metabolism by Nocardia opaca. Anthonie van Leewenhoek 34 417-432. 

Taniuchi H, M Hatanaka, S Kuno, O Hayashi, M Nakazima, N Kurihara (1964) Enzymatic formation of catechol from anthranilic acid. J Biol Ghent 239 2204-2211. 

Another multistep protocol that initially involves the formation of fused pyrimidines (quinazolines) has been described by Besson and coworkers in the context of synthesizing 8f-/-quinazolino[4,3-b]quinazolin-8-ones via double Niementowski condensation reactions (Scheme 6.250) [437]. In the first step of the sequence, an anthranilic acid was condensed with formamide (5.0 equivalents) under open-vessel microwave conditions (Niementowski condensation). Subsequent chlorination with excess POCl3, again under open-vessel conditions, produced the anticipated 4-chloro-quinazoline derivatives, which were subsequently condensed with anthranilic acids in acetic acid to produce the tetracyclic 8H-quinazolino[4,3-b]quinazolin-8-one target structures. The final condensation reactions were completed within 20 min under open-vessel reflux conditions (ca. 105 °C), but not surprisingly could also be performed within 10 min by sealed-vessel heating at 130 °C. 

Scheme III - Plausible sequence of formation of tryptanthrin from anthranillic acid and isatin...

Fig. 2.40. Plausible sequence of formation of indigotin from indican (I), of indirubin from indoxyl and isatin (II), and of tryptanthrin from anthranillic acid and isatin (III). Reprinted with permission from A. V. Muruganandam et al. [118].

The route of formation of the carbazole nucleus is still far from understood, and has been variously considered to arise from 3-prenylquinolone via a pathway involving shikimic acid (394) and mevalonic acid (MVA) (400) (Scheme 3.1) (1,112,362-366), anthranilic acid (397) and prephenic acid (404) via a pathway involving shikimic acid (394) (Scheme 3.2) (367), and also tryptophan (408) involving the mevalonate (400) pathway (Scheme 3.3) (133). All of these pathways lack experimental proof. However, based on the occurrence of the diverse carbazole alkaloids derived from anthranilic acid (397) in the family Rutaceae, the pathway... 

The biogenetic pathway proposed by Chakraborty for the formation of carbazole (1) and 3-methylcarbazole (2) proceeds through Af-phenylated anthranilic acid (406). This hypothesis is based on aromatic C-methylation of aniline with methionine, and originates from anthranilic acid (397) and prephenic acid (404). Until now, there are no N-phenylated anthranilic acid derivatives known naturally, therefore, this hypothesis is lacking substantial biogenetic evidence. However, the isolation of carbazole (1), 3-methylcarbazole (2), and several derivatives of 3-methylcarbazole... 

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 the condensations of o-aminohenzyl alcohol 376 or anthranilic acid 401 with 4,5-dichloro-l,2,3-dithiazolium chloride (Appel s salt) 402, imino-l,2,3-dithiazoles 403 were formed. Heating of the imino alcohol 403 (X = H2) in THE in the presence of NaH afforded an 11 1 mixture of 3,1-benzoxazine 404 and 3,1-benzothiazine 405 in moderate yield. Thermal cyclization of imino acid 403 (X = 0) resulted nearly quantitatively in formation of 3,1-henzoxazin-4-one 406 (Scheme 76) <1995CC1419, 1995J(P 1)2097, 1997SL704>. 

Condensation of anthrandic acid (77-1) with an iminoether represents another method for preparing quinazolones. The reaction with the iminoether (77-2) from 2-cyano-5-nitrofuran and ethanohc acid can be visualized as proceeding through the formation of the amidine from addition-elimination of anthranilic acid cycliza-tion then affords the observed product (77-3). This is then converted to chloride (77-4) in the usual way. Displacement of the newly introduced chlorine with diethanolamine leads to the formation of nifurquinazol (77-5) [86], one of the antibacterial nitrofmans (see Chapter 8). 

The discovery that the cyclization of one of the sulfonamide groups and the adjacent amine in classic monocyclic diuretics leads to an increase in potency is discussed in the next section. A similar increase in potency is also observed in the anthranilic acid based diuretics. Thus the fusion of anthranilic acid (87-1), which may show diuretic activity in its own right, with propionamide leads to the ring closure and formation of (87-2). Reduction of the unsaturation in the heterocyclic ring then affords the diuretic quinethazone (87-3) [97]. 

Pyrrolo[2, l-b]quinazolines (49) were obtained through the formation of their diazine ring by condensation of an anthranilic acid derivative with a pyrrole derivative such as O-alkylbutyrolactimes (48) [60GEPI088968 ... 

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