Anthranilic acid, condensation with

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>. 

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 ... 

Path A involves N-formylation of anthranilic acid, condensation of the resultant 2-formaminobenzoic acid with the amine followed by intramolecular amidation of the intermediate amidine to form the product. On the other hand, the amine instead of anthranalic acid may be formylated and go through the known Niementowski reaction (path B). When the reaction of 2-formamidobenzoic acid with aniline and the condensation of formanilide with anthralic acid were conducted under microwave irradiation, the desired 3-phenylquinazolin-4(3 JT)-one was obtained in both cases in a few minutes in 68-87% yield. 

An efficient method for the synthesis of 2-substituted benzoxazin-4-ones was performed by the condensation of anthranilic acid (436) with various orthoesters by classical heating for 1 2h to give 75 91% yields. But under MWI in an open vessel, a rapid formation of benzoxazin-4-ones 439 in high yields (76-94%) took place within 1-5 min (Scheme 86). The reaction may proceed through the imidic ester intermediate 437, which upon nucleophilic attack by the carboxyl oxygen produced the cycKzed intermediate 438 that then eliminated a molecule of alcohol to give 439 (97JCR(S)286). 

The cyclic dipeptide cyclopenin (12) has been neatly synthesised by condensation of a modified anthranilic acid moiety with phenylpyruvic acid. The reaction strategy (Scheme 2) was patterned on biogenetic considerations. 2-Nitrobenz-amide (13) condensed with phenylpyruvic acid to give the hippuric acid (14) the ester (15), upon iV-methylation, reduction, and cyclisation, gave the 3,10-dehydro-derivative (18), which had been converted previously into cyclopenin. 

The Niementowski quinazoline synthesis is the condensation of an anthranilic acid (1) with an amide (2) to produce a 4-keto-3,4-dihydro-quinazoline product (3). The reaction occurs under thermal conditions, and reaction temperatures > 100 °C are generally required. This reaction is also often referred to as the Niementowski reaction, and occasionally as the Niementowski 4-quinazolone synthesis or von Niementowski synthesis. ... 

From a biogenetic point of view, Robinson (4S) first postulated that the 9(lQ//)-acridinone skeleton should arise from the condensation of an anthranilic acid unit with three acetate units, leading, via a polyketoacid, to the tricyclic nucleus typically oxygenated at C-1 and C-3. Experimental support of this hypothesis was... 

The historical condensation of anthranilic acid (3) with phloroghicinol (206) to give 1,3-dihydroxyacridone (22) by Baczynski and von Niementowdd should be considered as Ae first biomimetic synthesis of an acridone alkaloid (284). The yield of the reaction was initially very poor, but was increased by subsequent modifications by Beck et al. (28S) and by Hlubucek et al. (286). More rec y. Smolders et al. described an efficient condensation of methyl anthranilate (207) with phloroglucinol, in the presence of 4-toluenesulfonic acid in l-hqitanol, which gave 22 in 80% yield (287). 

Phenylglycine-o-carboxylic acid. In a 750 ml. round-bottomed flask, fitted with a reflux condenser, place 14 g. of anthranilic acid (Section IV,170), 10 g. of chloroacetic acid, 20 g. of anhydrous sodium carbonate and 200 ml. of water. Reflux the mixture for. 3 hours, then pour into a beaker, cool, render shghtly acid with concentrated hy dro-chloric acid, and allow to stand overnight. Filter off the crude acid and wash it with water. Recrystalhse from hot water with the aid of a little decolourising carbon, and dry the acid at 100°. The yield of phenyl-glycine-o-carboxyhc acid, m.p. 208°, is 12 g. 

Isatin (190) is a compound with interesting chemistry. It can be iV-acetylated with acetic anhydride, iV-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 (81AG(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(P1)2004). 

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. 

Flufenamic acid (162) is a reasonably well-established NSAID (Non Steroidal Anti Inflammatory Drug). Alkylation of its potassiuni salt with the hydroxyethyl ethyl ether of ethylenechlo-rohydrin affords the latendated derivative etofenamate (163) [41]. Antiinflammatory activity is apparently retained when both rings in the fenamate series carry carboxyl groups. Thus, condensation of dichlorobenzoic acid 164 with anthranilic acid (165) by means of nucleophilic aromatic... 

Replacement of one of the benzene rings in a fenamic acid by pyridine interestingly leads to a compound which exhibits antiliypertensive rather than antiinflammatory activity. Preparation of this agent starts with nucleophilic aroniatic substitution of anthranilic acid (8) on 4-chloropyri-dine. The product (9) is converted to its acid chloride (10), and this is condensed with piperidine. There is thus obtained ofornine (11) f31. 

N-(m-methylmercapto-phenyl)-aniline (MP 59° to 61°C) is prepared by condensing m-methyl-mercapto-aniline (BP 163° to 165°C/16 mm Hg) with the potassium salt of o-chloro-benzoic acid and decarboxylating the resultant N-(m-methylmercapto-phenyl)-anthranilic acid (MP 139° to 141°C) by heating, and then distilling. 

Most condensations of this type start with 2-aminobenzoic acid (anthranilic acid) derivatives. In an early, extensive work on the synthesis and chemistry of dianthranilides", acid chlorides 1 were used as starting materials.2... 

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. 

The first anthraquinone vat dye containing an acridone ring system was synthesised in 1909 by Ullmann. The parent compound (6.89) can be made by condensation of 1-chloroanthraquinone with anthranilic acid in the presence of copper, followed by cyclodehydration in concentrated sulphuric acid (Scheme 6.17). 

Quinacridones are not the only industrially significant products. The list may be extended to include the derivative mentioned in Section 3.2.1.4, the linear trans-quinacridone quinone. There are two other synthetic pathways besides the hydroquinone method. The older method involves cyclization of the 2,5-bis-(2 -carboxyanilino-)-l, 4-benzoquinone 63 with concentrated sulfuric acid or polyphos-phoric acid at 150 to 200°C. The starting material 63 is obtained through condensation of 1,4-benzoquinone with anthranilic acid ... 

During the biosynthetic transformation, chorismate is the point of divergence for the biosynthesis of Phe, Tyr, Trp, and other amino acids containing aromatic groups. For example, the biosynthesis of Trp begins with the conversion of chorismate to anthranilate (Scheme 4(a)). A sequence of amination and aromatization reactions produces anthranilate, which is then condensed with phosphoribosylpyrophosphate. The intermediate is carried through a series of reactions to yield Trp (Scheme 4(b)). 

One of the early steps in an allergic reaction consists in the release of a series of endogenous compounds referred to as mediators from sensitized cells. The finding in the early 1960s that cromolyn sodium, still the only approved drug of this class, blunts this reaction has led to an intense search for additional examples. It is of interest that a relatively simple anthranilic acid derivative has shown mediator-release inhibiting activity. Reaction of 3,4-dimethoxybenzalde-hyde (167) with isatoic anhydride 168 gives the condensation product 169, which, upon hydrolysis, affords tranilast (170) (43]. 

The gallium(lll) triflate-mediated condensation of anthranilic acid with fluorinated ketones gave the corresponding 2,2-disubstituted l,2-dihydro-4//-3,l-benzoxazin-4-ones in high yields <20070L179>. 

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