Diazotization of anthranilic acid

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>. 

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). ... 

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 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). 

Benzyne, generated by the diazotization of anthranilic acid with isoamyl nitrite, is added to Gd Cs2 forming two isolable isomers of mono-adducts. Electrochemical measurements disclosed that the electronic structure of pristine Gd Cs2 has changed dramatically. Because of the high reactivity of benzyne, multiple adducts are not avoidable, even at lower temperatures [146]. 

In a bimolecular cycloaddition reaction 1-phenylbenzotriazole (369) is obtained from dehydrobenzene (by diazotization of anthranilic acid) and phenyl azide (64joc3733, 6SCB3142). The synthesis of 1-glucosylbenzotriazole from glucosyl azides and dehydrobenzene has been accomplished in this way, 5delding, for example, l-(2,3,4,6-tetra-0-acetyl-j8-D-glucopyranosyl)benzotriazole (370) (68jhc699>. 

The diazotization of anthranilic acid, a classic route to benzyne, when carried out in the presence of vinyl acetate, vinyl ethers or 1,1-dichloroethylene gives the expected benzocyclobutenes in about 40% yield. Despite the rather moderate yields this method represents a convenient route to multigram quantities of the parent compounds, benzocyclobutenol and benzocyclobutenone. The latter is easily converted to benzocyclobutene-1,2-dione. The diazotization sequence applied to 2-amino-3,6-dimeth-oxybenzoic acid and 1,1-dichloroethylene results in a 80% yield of 3, imethoxycyclobuten-l-one. Trapping of benzynes with other ethylene derivatives, and especially more substituted alkenes, has given generally poorer, variable results. ... 

Benzenediazonium-2-carboxylate and its substituted derivatives have been prepared by diazotization of anthranilic acids in the presence of hydrochloric acid followed by dehydrochlorination of the resultant diazonium carboxylate hydrochlorides with silver oxide. 

Dimethoxyethane is preferred as solvent for the generation of benzyne by aprotic diazotization of anthranilic acid with isoamyl nitrite." ... 

Trichloroacetic acid is recommended as catalyst in the diazotization of anthranilic acid for the preparation of benzenediazonium-2-carboxyIate, a benzyne precursor. ... 

Aprotic diazotization of anthranilic acid, usually with pentyl nitrite, gives benzyne via the reaction sequence shown in Scheme 1. The intermediate benzenediazonium-2-carboxylate (4) is explosively unstable, but if it is isolated by performing the first step at 0°C it provides a clean source of benzyne... 

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... 

Phenazine is similarly unreactive toward benzyne (by oxidation of 9), which gave only biphenylene and small amounts of unidentified highly colored products.81 On the other hand, the benzo[h]quinolizinium salt 175 reacts like anthracene with benzyne (generated by aprotic diazotization of anthranilic acid in refluxing acetonitrile) to give the Diels-Alder adduct 176 (78%).100 Aromatization of 176 to 9-(2-pyridyl)anthracene (177) is accomplished in refluxing acetic anhydride in the presence of sodium acetate. 

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... 

Simple pyrroles do not react as 4n components in Diels-Alder cycloadditions exposure of pyrrole to benzyne, for example, leads only to 2-phenylpyrrole, in low yield. However A-substitution, particularly with an electron-withdrawing group, does allow such reactions to occur, for example adducts with arynes are obtained using l-trimethylsilylpyrrole. Whereas pyrrole itself reacts with dimethyl acetylenedicar-boxylate only by a-substimtion, even at 15 kbar, ° A-acetyl- and A-alkoxycarbonyl-pyrroles give cycload-ducts, addition being much accelerated by high pressure or by aluminium chloride catalysis. The most popular A-substituted pyrrole in this context has been A-Boc-pyrrole, with benzyne (from diazotization of anthranilic acid) for example, a 60% yield of the cycloadduct is obtained. ... 

Sol 7. (d) Diazotization of anthranilic acid gives a diazonium salt, which on treatment with a mild base undergoes elimination of CO2 and N2 to give benzyne intermediate (I). It immediately undergoes Diels—Alder reaction to... 

Another q>pToach to the aoidone skeleton, developed by Watanabe et al. 314), was based on an earlio- obsravation that small amounts of aoidones woe formed when benzynes were generated by diazotization of anthranilic acids 315-317). The acridones result in these cases from the reaction of benzynes with undiazotized anthranilic acids. Therefore, a new route was developed through tandem metallation synthesis. The lithium salt of methyl iV-methylanthranilate (250) could be easily coupled with the benzynes 251, 252, and 253, generated by treatment of chlorobenzene, 1 -bromo-2-methoxybenzene, and l-chloro-3,5-... 

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