Diazotization of heteroaromatic amines

The diazotization of heteroaromatic amines is a ticklish procedure. In spite of the great increase in interest for disperse dyes based on heterocyclic diazo components,... 

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the five-membered systems the amino-azoles (pyrroles, diazoles, triazoles, tetrazoles, oxazoles, isooxazoles, thia-, selena-, and dithiazoles) have all been diazotized. In general, diazotization in dilute mineral acid is possible, but diazotization in concentrated sulfuric acid (nitrosylsulfuric acid, see Sec. 2.2) or in organic solvents using an ester of nitrous acid (ethyl or isopentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

It is appropriate to add here some comments on diazotization in anhydrous carboxylic acids. They may be relevant for the diazotization of heteroaromatic amines carried out in acetic acid/propionic acid mixtures (Sec. 2.2). Extensive studies by Casado et al. (1983, 1984) showed that in nitrosation of secondary amines the nitrosyl ion, nitrosyl acetate, and dinitrogen trioxide are formed, and all three may act as nitrosating agents. The results do not, however, account for the considerable improvement that is claimed in the patent literature (Weaver and Shuttleworth, 1982) to result from the addition of carboxylic acids in the diazotization of heteroaromatic amines. 

In the context of the stability of the nitrosoamine intermediate in the diazotization of heteroaromatic amines relative to that in the case of aromatic amines, the reversibility of diazotization has to be considered. To the best of our knowledge the reverse reaction of a diazotization of an aromatic amine has never been observed in acidic solutions. This fact is the basis of the well-known method for the quantitative analysis of aromatic amines by titration with a calibrated solution of sodium nitrite (see Sec. 3.3). With heteroaromatic amines, however, it has been reported several times that, when using amine and sodium nitrite in the stoichiometric ratio 1 1, after completion of the reaction nitrous acid can still be detected with Kl-starch paper,... 

The diazotization of heteroaromatic amines is a ticklish procedure. In spite of the great increase in interest for disperse dyes based on heterocyclic diazo components, little systematic knowledge is available. In a review of such diazo components13 practically nothing is mentioned on suitable methods of diazotization and on yields (which are in part low). The somewhat older review of Butler14 is, in this respect, more informative. So too is the section on synthesis in the general review on diazoazoles by Cirrincione and coworkers15. 

The rates of diazotizations in nitrosylsulfuric acid can be increased favorably by the addition of acetic or propionic acid. A mixture of the two acids is frequently used as an additive in diazotizations of heteroaromatic amines, as it has a lower melting point than acetic acid (0 °C or lower), but little is mentioned about it in the scientific literature... 

Benzylic oxidation of heterocycles with quinones 80YGK1163. Diazotization of heteroaromatic amines 83UK777. 

The reversibility of aromatic diazotization in methanol may indicate that the intermediate corresponding to the diazohydroxide (3.9 in Scheme 3-36), i. e., the (Z)-or (is)-diazomethyl ether (Ar — N2 — OCH3), may be the cause of the reversibility. In contrast to the diazohydroxide this compound cannot be stabilized by deprotonation. It can be protonated and then dissociates into a diazonium ion and a methanol molecule. This reaction is relatively slow (Masoud and Ishak, 1988) and therefore the reverse reaction of the diazomethyl ether to the amine may be competitive. Similarly the reversibility of heteroaromatic amine diazotizations with a ring nitrogen in the a-position may be due to the stabilization of the intermediate (Z)-diazohydroxide, hydrogen-bonded to that ring nitrogen (Butler, 1975). However, this explanation is not yet supported by experimental data. 

The diazonium ions 13 with electron-withdrawing substituents are not h texoaromatic compounds and therefore do not strictly come within the scope of this chapter. They are formally related to the alkenediazonium ions. Nevertheless, they are discussed here because in their properties they bear a close resemblance to heteroaromatic and arenedi-azonium ions rather than to alkenediazonium ions. In particular they can be obtained by direct diazotization of the amines, they are stable in an aqueous medium and they are capable of undergoing an azo coupling reaction. 

The foimation of aromatic diazonium salts from aromatic primary amines is one of the oldest synthetic procedures in organic chemistry. Methods based on nitrosation of amine with nitrous acid in aqueous solution are die best known, but diere are variants which are of particular use widi weakly basic amines and for the isolation of diazonium salts fiom nonaqueous media. General reviews include a book by Saunders and AUen and a survey of preparative methods by Schank. There ate also reviews on the diazotization of heteroaromatic primary amines and on the diazotization of weakly basic amines in strongly acidic media. The diazotization process (Scheme 11) goes by way of a primary nitrosamine. 

Aromatic diazonium compounds became industrially very important after Griess (1866a) discovered in 1861/62 the azo coupling reaction, by which the first azo dye was made by C. A. Martius in 1865 (see review by Smith, 1907). This is still the most important industrial reaction of diazo compounds. Hantzsch and Traumann (1888) discovered that a heteroaromatic amine, namely 2-aminothiazole, can also be diazotized. Heteroaromatic diazonium compounds were, however, only used for azo dyes much later, to a small extent in the 1930 s, but intensively since the 1950 s (see Zollinger, 1991, Ch. 7). 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

In certain cases where the heteroaromatic amine is insufficiently soluble in aqueous acid, it can be dissolved in the minimum volume of an organic solvent miscible with water. Dilute mineral acid and a solution of sodium nitrite are then added. An example is the diazotization of 2-phenyl-3-amino-4-acetyl-5-methyl-pyrrole (Dattolo et al., 1983). 

Diazotization of A-heteroaromatic amines may result in hydrolytic opening of the heterocycle, as shown by the examples in Schemes 6-36 and 6-37 which were studied by the group of Ulsaker and Undheim (Hagen et al., 1974 Ranger et al., 1978) and by Davies and Jones (1970). 

In Section 3.4 we discussed the problem of reversibility of diazotization of aromatic and heteroaromatic amines. Simple stoichiometric considerations indicate that the reverse reaction (ArNJ -> ArNH2) may take place under strongly acidic conditions. Experimentally the reverse reaction was found only with heteroaromatic diazonium salts (Kavalek et al., 1989). Reaction conditions of hydroxy-de-diazonia-tion are comparable to those used for the reverse reactions of diazotization (e.g., 10 m H2S04, but at 0°C for the formation of 2-amino-5-phenyl-l,3,4-thiadiazol from the corresponding diazonium salt, Kavalek et al., 1979). So far as we know, however, amines have never been detected in aromatic hydroxy-de-diazoniations, not even in small amounts. 

Bersier and coworkers29 published a list of 20 aromatic and heteroaromatic amines whose stabilities in diazotization systems have been investigated. Aqueous systems are harmless, even with amines containing one or two nitro groups (provided that they can be diazotized at all in water). In 96% sulfuric acid, diazotizations of aminoanthraquinones are not dangerous this is also the case for heteroaromatic amines in mixtures of sulfuric acid... 

Diazatrimethine dyes have been prepared by oxidative coupling of a heterocyclic hydrazine with an active methylenic heterocycle as in the yellow dye (31). Alternatively they may be prepared by diazotization of an aromatic or heteroaromatic amine followed... 

This procedure has found wdde application in the synthesis of aromatic and heteroaromatic azides the yields are usually high and often quantitative. General procedures have been developed by Smith and co-workers the method of choice mainly being determined by the basicity of the amine involved or the solubility of its salts. Weakly basic amines, for example, are diazotized with amyl nitrite in an acetic acid-concentrated sulphuric acid mixture and aqueous sodium azide is subsequently added. Amines which form insoluble salts with common mineral acids zu e converted to the more soluble 2-hydroxyethanesulphonic acid salts prior to diazotization. This procedure has been applied in the diazotization of the N-(aminophenyl)phthalimides (254). Treatment of the resulting diazonium compounds (255) with hydrazoic acid and removal of the protecting phthalimido group affords the otherwise inaccessible azidoanilines (equation 134). Some representative examples of azides recently synthesized by these methods, are shown in Table 11. 

Synthesis of aromatic azides by nitrosation of hydrazine derivatives has usually been employed in preference to procedures involving diazotization of a primary amine only in cases where this latter procedure is of a difficult or uncertain nature. For this reason mzmy heteroaromatic azides have been synthesized by nitrosation of their readily obtainable hydrazino derivatives (Table 18). 

The preparation of aromatic and heteroaromatic diazonium compounds follows, with very few exceptions, the same basic pattern, namely the diazotization of the corresponding amines. Under appropriate conditions (temperature and acidity), formation of the desired diazonium ion is a rapid and smooth process with a yield of almost 100%. Diazotization may even be applied as a titration method (see Zollinger, 1994, Sect. 2.1). 

A simple method has been devised for the synthesis of aromatic or heteroaromatic aryl(alkyl) sulphides, in which the aromatic or heteroaromatic amine is diazotized in the presence of a diaryi(alkyl)sulphide. ... 

Diazotization of aromatic and heteroaromatic amines and subsequent treatment with sodium azide has been used for the synthesis of aryl azide (Scheme 3.34). This reaction does not involve the cleavage of the carbon-heteroatom bond. Instead, after the addition of the azide onto the diazonium ion, an open pentazene or a cyclic pentazole is formed, followed by the release of nitrogen to yield the aryl This approach can be... 

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