Pentyl nitrite diazotization

The diazotization of heteroaromatic amines is basically analogous to that of aromatic amines. Among the hve-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 below) or in organic solvents using an ester of nitrous acid (ethyl or 2-pentyl nitrite) is often preferable. Amino derivatives of aromatic heterocycles without ring nitrogen (furan and thiophene) can also be diazotized. 

Diazotization in organic solvents allows solid diazonium salts to be isolated. Diazotization can be carried out using an ester of nitrous acid, such as pentyl nitrite, in a solvent such as acetic acid or methanol. A procedure has also been described for isolating diazonium tetrafluoroborates, in excellent yield, by carrying out the diazotization with boron trifluoride etherate and f-butyl nitrite in ether or dichlorometh-ane at low temperature. Another method for the preparation of a variety of diazonium salts in a nonaqueous medium makes use of the chemistry of bis(trimethylsilyl)amines (8). These compounds react in dichloromethane with nitrosyl chloride and other nitrosating agents which are generated in situ. Thus, benzenediazonium chloride was isolated (96%) from bis(trimethylsilyl)aniline. 

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... 

Two syntheses of benzocinnoline Ar-imines have been described recently.78 They can be prepared from benzocinnoline and hydroxy lamine-O-sulfonic acid or by diazotization of 2,2 -diaminobiphenyl with pentyl nitrite or JV-nitrosodiphenylamine. Diazotization of the diamine presumably proceeds via the triazepine 48, which is isomeric with unsubstituted benzocinnoline iV-imine. Benzocinnoline iV-imine itself, the only unsubstituted iV-imine so far isolated, was prepared from benzocinnoline and hydroxylamine-O-sulfonic acid. Under similar conditions, quaternary IV-amino salts were isolated from the other iV-heterocycles. The unsubstituted Ar-imine can be converted easily into the acyl, sulfonyl, and 2,4-dinitrophenyl derivatives (Scheme 3). 

As the proton release is often too slow under the acidic conditions used for the diazotization of aromatic amines, syntheses of aliphatic diazo compounds by this method are carried out without an excess of mineral acid. Usually, equimolar amounts of amine, HCl and NaN02, or amine and NOCl, are used. A better alternative is nitrosation with pentyl nitrite in the presence of up to 30% acetic acid, as found by Takamura et al. (1975). Yields higher than 60% were obtained with a-amino-substituted esters of some aliphatic carboxylic acids. 

Insertion is rather a common reaction of a carbocation, if it is located close to a hydrocarbon group, as shown first by de Vries and Winstein (1960). Elegant evidence for such a reaction was given by Oki et al. (1990) in the diazotization of the ap- and 5C-rotamers 7.143 and 7.145 of a triptycene compound with 2-pentyl nitrite and acetic acid in benzene. Both gave the expected elimination and acetolysis products, but also the compounds 7.144 and, in the case of the 5C-rotamer, 7.146, in yields as given in Schemes (7-50)-(7-51). These products are formed by insertion into a CarH bond (7.144) and into a methyl CH bond (7.146). The last-mentioned compound is obviously a product of a proximity effect (see also Oki, 1990). 

Diazotetrazole (16) was obtained by dropwise addition of 2-pentyl nitrite to a solution of 5-amino-l//-tetrazole in a 4 1 mixture of tetrahydrofuran and aqueous hydrochloric acid. The diazonium chloride can be extracted into ether. Shevlin obtained the extremely explosive solid diazonium salt (16) by evaporation of that solution. He has recommended that not more than 0.75 mmol of diazonium salt be isolated at one time. An explosion during the diazotization of 5-aminotetrazole on a laboratory scale was described by Gray and coworkers. The structure 17 (equation 5) indicates clearly that this diazo compound may have the tendency to decompose into atomic carbon and three equivalents of dinitrogen—a reaction which is clearly highly exothermic. The decomposition of the tetrazole-5-diazonium chloride (16) has been studied by Shevlin by coating the salt on the walls of a 500 ml flask in the presence of two substrates, ethene and ethylene oxide. With ethene the products found after heating the flask to 80 °C are shown in equation 6, and with ethylene oxide in equation 7. The products correspond to those found with atomic carbon formed by completely different methods (see references cited by Shevlin). 

In most cases diazonium salts are not isolated, but are converted into products by reactions that can be carried out in situ. Moreover, it is actually recommended not to isolate these salts, not even for purification purposes, as many of them have a tendency to explode. In addition, the high solubility of most diazonium salts in water makes precipitation from this medium difficult. Therefore, to obtain solid diazonium salts the recommended method for many decades was to carry out diazotizations in ethanol followed by precipitation with ether. As inorganic salts of nitrous acid are scarcely soluble in ethanol, Knoevenagel recommended alkyl nitrites (ethyl or 2-pentyl nitrite) as diazotization reagents as long ago as 1890. Various other solvents have subsequently been used for diazotizations with alkyl nitrites (see Saunders and Allen ), but as a method for obtaining solid diazonium salts this has been superseded by the isolation of diazonium tetrafluoroborates and, to a lesser degree, of hexafluorophosphates. 

The use of dry aryldiazonium salts of naphthalene-1-sulfonic [70], naphthalene-1,5-disulfonic [70], ZnCl2 complex [70], hexafluorophosphoric or tetrafluoroboric acid [61] in non-aqueous medium under as mild as possible reaction conditions is substantial to reach higher yields of biaryls. An alternative method for non-aqueous GBH reaction is the aprotic diazotation of aromatic amines with alkyl nitrites such as butyl or pentyl nitrite with subsequent arylation of aromatic compound, as demonstrated by Cadogan [71,72]. This method is realized by simple heating the mixture of aromatic amine, alkyl nitrite and liquid arene at an elevated temperature. When a mixture of 3-aminopyridine (46), benzene and pentyl nitrite is heated at reflux, 3-phenylpyridine (47) is obtained with a 55% yield [71], Scheme 16. 

Phenyl4-pyridone has been prepared from 4-metho 3-nitr<5(yridineby a diazotization of 3-amino-4-methoxypyiidine (XII-739) with pentyl nitrite in the presence of benzene and in the absence of added acid. ... 

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