Anthranilic acid diazotization

Anisole, chlorination with sulfuryl chloride, 47, 23, 49,16 Anisole, /i-a-mcHLORO-, 49,16 Anthranilic acid, diazotization with isoamyl nitrite and trichloroacetic acid, 48,13, IS... 

Tetrahydrofuran is widely employed as a solvent for reactions involving benzyne, yet it has been shown to be attacked by benzyne (from anthranilic acid diazotized in situ) to give products derived via the betaine 47.52 In the presence of water 48 and 49 are obtained (23% and 8%, respectively), whereas under anhydrous conditions the main product is 50 (17%) by reaction of 47... 

The angularly fused pyridazino[l,6- ]quinazolines were prepared by tandem [6+0 (a), 6+0 (7)] cyclization of functionalized, diazotized anthranilic acid derivatives. Depending on the order of reacting ethyl benzoylacetate, malonitrile, and the diazotized anthranilonitrile, the pyridazino[l,6- ]quinazolines 103 or 105 were obtained by alkaline or thermal cyclizations, respectively (Scheme 11) <2001T1813>. 

Benzyne generated in situ by diazotization of anthranilic acid adds readily to aminides 172 to provide cycloadducts 171. Introduction of a nitro group into para position of the phenyl ring on the nitrogen terminus of the 1,3-dipole (X2 = N02) stabilizes the system and results in higher yields of product 171 (70% vs. 50% forX2 = H). Electron-deficient imines react also with aminides 172, but the yields of isolated adducts 173 are relatively low (10-26%) (Scheme 19) <2003ARK(vii)110>. 

Methyl red was first prepared 1 by diazotization of anthranilic acid in alcoholic solution, the product being allowed to react with dimethylaniline in the same solvent. It has been stated 2 that this process does not work satisfactorily and yields a different product, of brownish-red color. 

Benzotriazole and its derivatives are usually obtained by diazotization of o-phenylenediamines as discussed in Section 4.01.8.3 and in CHEC-1 <84CHEC-i(5)722>. Substituted o-phenylenediamines (e.g., 849) similarly give 1-substituted benzotriazoles (850) upon treatment with NaNOz (Equation (87)) <92JHC1519>. 1-Arylbenzotriazoles are alternatively synthesized from the cycloaddition of an aryl azide to benzyne or substituted benzynes, generated from the diazotization of anthranilic acid or its appropriately substituted derivatives (Scheme 169) <86CC399,87JCS(Pl)403, CHEC-i>. 

Diazotization of anthranilamide and its derivatives is the most common and widely exploited reaction for the preparation of 1,2,3-benzo-triazine derivatives. The reasons for this are 3-fold (i) many nuclear substituted anthranilic acid derivatives are readily available (ii) the diazotization reactions generally proceed smoothly and in high yield, and the product triazinones are usually very stable and easily handled and (iii) many 3-substituted l,2,3-benzotriazin-4(3i/)-ones have been found to possess a wide range of pronounced pharmacological activity, while others undergo a number of very interesting chemical transformations, and hence a very large number of these compounds have been prepared. 

Acylhydrazides of anthranilic acid (35, R = NHCOR ) give 3-acylamino-l,2,3-benzotriazin-4(3H)-ones (10, R = NHCOR on treatment with nitrous acid. The triazine hydroxamic acid (40) and its benzo-substituted derivatives are available by diazotization of the corresponding o-aminobenzohydroxamic acids. The pyrido[2,3-e]triazine analog (41) was prepared similarly from 3-aminoisonicotino-hydroxamic acid, but the isomeric 2-aminonicotinohydroxamic acid failed to react under the same conditions to give 42. ... 

When benzyne is generated by aprotic diazotization of anthranilic acid in boiling 1,2-dimethoxyethane in the presence of substituted benzene-2-diazo 1-oxides (o-quinonediazides), dibenzofurans are obtained in moderate yields (Scheme 64). ... 

The thermal decomposition of diazotized anthranilic acid in acetone led to carbazole 328 as well as to 329, benzoic acid, and o-biphenylene. The 329... 

The melting point of the />-toluenesulfonylanthranilic acid is not a good criterion of purity because the />-toluenesulfonic acid salt of anthranilic acid has about the same value. The neutral equivalents are widely different 154 for the salt and 291 for p-toluenesulfonylanthranilic acid. The compound obtained in this preparation gives a negative test for anthranilic acid on diazotization and treatment with alkaline /3-naphthol solution. The probable impurity is the sodium salt of -toluene-sulfonylanthranilic acid. 

Diphenic acid has been prepared by the reduction of diazotized anthranilic acid with cuprous ion,5 Ullman coupling of potassium... 

The two heterocyclic rings of this system (485) were formed upon coupling salts of diazotized anthranilic acid (87JHC227) or diazotized anthranilic acid ester (88MI1) with butenonitriles. 

B. Diazotization of Anthranilic Acid.—To 100 g. (0.73 mole) of anthranilic acid (m.p. 143-1440) in a 1.5-I. beaker arranged for vigorous mechanical stirring and efficient external cooling are added 300 cc. of distilled water and 133 cc. of glacial acetic acid (2.3 moles) (Note 1). A solution of 51 g. of sodium nitrite (0.74 mole) in 200 cc. of distilled water is slowly added from a separatory funnel during about forty minutes (Note 2). 

In almost all samples of commercial anthranilic acid, even though showing the correct melting point, a small amount of insoluble material remains on diazotization. The clear liquor should be removed from this by decantation. 

Lester Friedman and Frauds M. Logullo prepared substituted benzynes by diazotizing substituted anthranilic acid. This is a mild, room-temperature reaction which permits simultaneous reactions of the benzynes with suitable acceptors to prepare halogen. —NO , — ClL. and —OCH3 derivatives. They have also prepared new heterocyclic arynes, such as 3-pyridine from 3-amino-isonicotinic add. 

Carboxy-phenyl] 3(oder l) cyanguanyl -triazen-(l) 2- [Cyanoguanyl-triazeno] -benzoesaure or [2-Carboxy-benzoldiazo] dicyandiamid in Ger), HOOC.C6H4,N N.NH.C-( NH).NH.CN mw 232.20 N 36.20% yel crysts (from MeOH), mp dec ca 98° readily sol in hot ale si sol in benz, eth or chlf insol in w was prepd by treating diazotized anthranilic acid with dicyandiamid in alksoln.Its Silver salt... 

V-Hydroxycarbazole (326) was first postulated (64JOC2808) as an intermediate in the reaction of benzyne with nitrosobenzene, which gave N-phenylcarbazole. Later it was obtained in 1% yield from diazotized anthranilic acid and nitrosobenzene, while tetrahalogenated benzynes,... 

Diphenic acid has been prepared by the reduction of diazotized anthranilic acid with cuprous ion,6 Ullman coupling of potassium o-bromobenzoate,6 and oxidation of phenanthrene or phen-anthrenequinone with various oxidizing agents.7 The latter methods have been reviewed recently.7 The ozonolysis method has also been carried out in solvents 8 that do not react with the zwitterion intermediate. ... 

Diphenic acid was first prepared by oxidizing phenanthrene-quinone with chromic acid.1 Many later workers2 have modified this process in minor details. Vorlander and Meyer 3 were the first to prepare diphenic acid from diazotized anthranilic acid and cuprous oxide, but their process is not well adapted to large scale preparation. Inasmuch as pure phenanthrene is now very difficult to obtain in quantity, the present process was devised for relatively large scale operation. 

It is not possible to prepare biaryls containing a free carboxyl group directly by the diazo reaction. No biaryl is formed when (a) diazotized aniline and sodium benzoate, (b) diazotized anthranilic acid and aqueous sodium benzoate, or (c) diazotized anthranilic acid and benzene are used as components in the reaction.13 On the other hand, the reaction proceeds normally if methyl benzoate is used in reaction (a) or when methyl anthranilate replaces the anthranilic acid in (b) and in (c). The success of the diazohydroxide reaction appears to lie in the ability of the non-aqueous liquid to extract the reactive diazo compound from the aqueous layer.4 However, esters and nitriles can be prepared from esters of aromatic amino acids and cyanoanilines and also by coupling with esters of aromatic acids, and from the products the acids can be obtained by hydrolysis. By coupling N-nitrosoacetanilide with ethyl phthalate, ethyl 4-phenylphthalate (VIII) is formed in 37% yield. 

The products obtained from esters of anthranilic acid and substituted anthranilic acids are of interest because fluorenones can be prepared from them. From diazotized methyl anthranilate and benzene, 2-carbometh-oxybiphenyl is obtained in 24% yield. Hydrolysis affords 2-biphenylcar-boxylic acid, which can be cyclized to fluorenone. By this procedure, a number of 2- and 3-substituted fluorenones have been prepared.16 Thus, 3-chlorofluorenone was prepared from methyl 4-chloroanthranilate and benzene through the following steps. 

The above procedure is derived from the work of Atkinson and Lawler 6 but employs a more suitable reducing agent than that7 previously used to convert diazotized anthranilic acid to diphenic acid. The product can be resolved into its optically active forms,6 which are stable to racemization. 

In Chapter 23 we met the remarkable intermediate benzyne and mentioned that convincing evidence for its existence was the trapping by a Diels-Alder reaction. An ideal method for generating benzyne for this purpose is the diazotization of anthranilic acid (2-aminobenzoic acid). 

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