Aprotic diazotization

Benzo-l,2,3-triazin-4-ones with the general structure 6.54 (X = O, S, or H2) are obtained by diazotization of the appropriate aniline derivatives 6.53 (Scheme 6-38). In polar aprotic solvents (e. g., nitrobenzene) the reverse reaction takes place to give the diazonium ion (for an example see Kullick, 1966). Diazotization of 1,8-diamino-naphthalene yields l-i/-naphthol[l,8-cfe]triazine (6.55 Tavs et al., 1967). In concentrated HC1 the triazine ring is opened again. 

Before discussing Beckwith s data on that basis, a brief mention must be made of investigations by Lown s group (Naghipur et al., 1989, 1990, and other papers cited there) who claim to have observed the formation of benzoxathiete (10.63) and its valence isomer monothio-l,2-benzoquinone (10.64) in the aprotic diazotization of 2-[(2,-acetoxyethyl)sulfinyl]aniline (10.62). Scheme 10-82 is an abbreviated form of the mechanism proposed by the authors. A more detailed experimental study is clearly required. 

Amines which are considerably or entirely insoluble in water are dissolved in glacial acetic acid or in other organic media, possibly mixed with water e.g., alcohols or aprotic solvents. Addition of acid is followed by a typical diazotization reaction in an aqueous sodium nitrite solution. Other possible sources of the nitrosating species NO include nitrosylsulfuric acid, nitrosylchloride, alkylnitrite, and nitrous gases. 

Starting materials which are only sparingly soluble in water may require solvents that are either partially or entirely organic. Diazotization can either be carried out as usual with an aqueous sodium nitrite solution, or alternatively with nitrosylsul-furic acid or an organic nitrite. Appropriate solvents must be stable to the reactants. Examples include aromatic hydrocarbons, chlorohydrocarbons, glycol ethers, nitriles, esters, and dipolar aprotic solvents, such as dimethyl formamide, dimethyl sulfone, tetramethylene sulfone, tetramethyl urea, and N-methylpyrroli-done. 

The compounds are obtained by coupling diazotized 1-aminoanthraquinone onto 2-hydroxy-3-naphthoic acid, followed by separation, drying, and conversion into the azo dye acid chloride. Condensation with amines (structure 81) is achieved in an aprotic organic solvent. 

Aprotic diazotization of 86 (R = Me or Ph) produced 55% of thianthrene and lesser amounts of 1-phenylthio- (or methylthio) dibenzothiophen (Scheme 14) together with deaminated products. Comparable yields of 2-methyl-, 2-methoxy-, 2,7-dichloro- and 2,8-dichlorothianthrenes were obtained using this synthetic route. It is suggested that ring closure involves an intramolecular homolytic substitution at sulfur with loss of the 5-substituent as a radical [74JCS(P1)1272]. 

From limited data the generalization has been made that this method fails for the synthesis of 1-substituted dibenzofurans and for the synthesis of 4-substituted dibenzofurans unless the amino group and the potential 4-substituent are in the same ring. These generalizations are not substantiated in the synthesis of polychlorodibenzofurans. Polychloro-2-phenoxy-anilines are poorly soluble and nonbasic so that the usual method is precluded. In these cases aprotic diazotization with isopentyl nitrite in tetrachloroethylene at 80 C is the method of choice. Yields, as determined by GLC, are usually of the order of 40-50%. The yields of pure isolated... 

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). ... 

In competitive studies (73IJS295, 74AHC(16)123) using aprotic diazotization of aniline to generate phenyl radicals, it has been shown that the relative rates of phenylation for furan and thiophene compared to benzene are 11.5 and 2.6, respectively. The partial rate factors... 

Heteroaryl radicals, generated by aprotic diazotization of heteroarylamines, have been reacted with thiophene to form the heterylthiophenes in 20-50% yields (75JOC3183, 78HCA2941). The 2/3 isomer ratio was generally about 85 15. Other heterylthiophenes have been prepared by photolysis of the iodoheteroaromatic compound in a solution of thiophene in acetonitrile thus the 2-(5-pyrimidinyl)thiophene (224) was obtained in 58% yield (with 2% of the 3-isomer) (77JCS(Pl)62l) and 2-(3-pyridinyl)thiophene (225) in 42% yield (2/3 isomer ratio 7 1) (72CC594). 

Cleavage of the S—S bond of (40) also occurs on reaction with phenyl radicals obtained by decomposition of A-nitrosoacetanilide or aprotic diazotization of aniline. The main... 

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

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... 

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... 

Benzyne and substituted benzynes, generated by thermal decomposition of 2-carboxybenzenediazonium chloride or by aprotic diazotization of appropriate anthranic acids, reacted with a variety of thiophene dioxides to produce naphthalene derivatives generally in moderate yields (Scheme 56) [34,159]. In two cases, the naphthalenes so produced further reacted with benzyne to give benzobarrelene derivatives. 

Uniquely, 3,l,2-benzothiadiazin-4-one (42) can be obtained by diazotization of thioanthranilic acid under aprotic conditions <72JA8505>. 

Friedman and his co-workers191 have been responsible for a new development on diazotization by an alkyl nitrite and an equivalent amount of acetic acid in an aprotic solvent such as chloroform or benzene, a primary amine gives a weakly solvated cation whose reactions resemble those of carbenes. For example, isobutylamine in this way affords about 30% of mixed hydrocarbons containing about 15% of methylcyclopropane ... 

Benzyne is a necessary intermediate in the diazotization of 2-[(2-acetoxyethyl)sulfinyl(and sulfonyl)]anilines 107 and 116, but a detailed study of the way it is formed gave some surprises . Products from the aprotic diazotization of 107 included biphenylene 67 and dibenzo-l,4-thioxin 112. EPR evidence for radical intermediates was obtained. Formation of 112 requires cleavage of the S—O bond, most probably via benzoxathiete 110 as shown. Although yields of 67 and 112 were low, when the diazotization was carried out in the presence of benzyne traps such as diphenylisobenzofuran or anthracene, respectable yields (30-40%) of the corresponding benzyne cycloadducts were obtained. 

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