Amino acids, isolation diazo compounds

The treatment of 3-amino-1,2,4-triazine 2-oxides 1 or 3-amino-1,2,4-benzotri-azine 1-oxides 29 with nitrous acid proceeds as a diazotization reaction, but the diazo compounds have never been isolated owing to the easy displacement of the di-azo group with nucleophiles. Thus the reaction of 3-amino-1,2,4-triazine 2-oxides 1 with sodium nitrite in hydrochloric or hydrobromic acids leads to the corresponding 3-halogen-1,2,4-tiiazine 2-oxides 119 or 3-bromo-l,2,4-benzotriazine 1-oxides 120 (77JOC546, 82JOC3886). 

Shortly after Perkin had produced the first commercially successful dyestuff, a discovery was made which led to what is now the dominant chemical class of dyestuffs, the azo dyes. This development stemmed from the work of Peter Griess, who in 1858 passed nitrous fumes (which correspond to the formula N203) into a cold alcoholic solution of 2-aminO 4,6 dinitrophenol (picramic acid) and isolated a cationic product, the properties of which showed it to be a member of a new class of compounds [1]. Griess extended his investigations to other primary aromatic amines and showed his reaction to be generally applicable. He named the products diazo compounds and the reaction came to be known as the diazotisation reaction. This reaction can be represented most simply by Scheme 4.1, in which HX stands for a strong monobasic acid and Ar is any aromatic or heteroaromatic nucleus. 

Reduction of these nitro-acids gives the amino-acids, the usual reducing agent being ferrous sulphate in alkaline solution, but in one ease sodium amalgam in methyl alcohol has been used. The hydroxy-acids are isolated from the amino-acids by the aid of the diazo reaction. The acids are crystalline solids, usually soluble in water. The following scheme shows the compounds known ... 

The optimum temperature for simple arylamines is 0-2°, for m-haloaryl-amines 0-5°, and for benzidines, naphthylamines, and o- and / -haloarylamines 10-12°. In isolated cases higher temperatures are used, e.g., 34° for / -nitro-aniline and 40° for o-anisidine. The end-point of the reaction is determined by testing for an excess of nitrous acid with potassium iodide-starch paper. Amino sulfonic acids are no longer used to remove the excess of nitrous acid since they react with reactive diazo compounds.244... 

As mentioned in Section 1.1, the first diazotization of amines, followed by dediazoniation, was carried out by Piria in 1848, well before Griess discovered and isolated aromatic diazo compounds (1858). Piria added an impure HNO3 —HCl solution to a mixture of asparagine and aspartic acid in water and obtained malic acid (7-1). It was not possible for Piria, however, to realize that the primary reaction products were diazonium ions. Yet, Piria s process was one of the few types of reaction via aliphatic diazonium ions that became important for synthetic purposes, after Ingold s group (Brewster et al., 1950) discovered that a-amino acids undergo clean retentive deamination (see Sect. 7.7). 

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 its pure form at room temperature, diazomethane is a pale yellow explosive gas and is almost never isolated as such. It s typically prepared as a solution in diethyl ether. Nowadays, many organic chemists have altogether dispensed with using the parent diazomethane, preferring the much safer trimethylsilyldiazomethane instead. Another common diazo compound is ethyl diazoacetate (EDA), prepared from the ethyl ester of the amino acid glycine as follows ... 

Diazopentane-2,4-dione added to 4-amino-3,5-dimethylisoxazole in glacial acetic acid, heated 2 hrs. at ca. 50°, stored 2 days at room temp., more diazo compound added, and the product isolated after 3 more days 4-acetyl-5-methyl-l-(3,5-dimethylisoxazol-4 yl)-1,2,3-triazole. Y 72%. A. J. Boulton, and A. R. Katritzky, Soc. 1962, 2083. 

Primary amino groups attached to azole rings react normally with nitrous acid to give diazonium compounds via primary nitroso compounds. However, the azole series shows two special characteristics the primary nitroso compounds can be stable enough to be isolated, and diazo anhydrides are formed easily from azoles containing ring NH groups. 

Following their work on the synthesis of the parent compound 2,6-naphthyridine (105) (105). Taurins and Li reported their work in full (107) and at the same time reported a synthesis of the 4-methyl derivative 104, isolated by Harkiss and Swift (62). 4-Cyano-3-pyridyl-acetonitrile (275) was methylated (CFLI-NaOQHs) in the side chain to afford 2-(4-cyano-3-pyridyl)propionitrile (276), which was treated with hydrogen bromide in ether to afford 3-amino-l-bromo-4-methyl-2,6-naphthyridine (277). Diazo-tization/bromination and replacement of the bromine groups with hydrazine gave 278, and reaction with CuS04 in acetic acid afforded 4-methyl-2,6-naphthyridine (98) (Scheme 23) (107), whose spectroscopic properties were identical with those reported previously (62,63). 

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