Diazotization of amines

Diazotization of Amines with Alkali Nitrite in Dilute Aqueous Mineral Acids... 

Diazotization of amines for Meerwein reactions is almost always carried out using an aqueous solution of HC1. Meerwein et al. observed in their pioneering investigation of 1939 that the use of sulfuric or nitric acid for diazotization failed. 

Ethyl 3-azido-l-methyl-177-indole-2-carboxylate 361 is prepared in 70% yield by diazotization of amine 360 followed by substitution of the created diazonium group with sodium azide. In cycloadditions with nitrile anions, azide 361 forms triazole intermediates 362. However, under the reaction conditions, cyclocondensation of the amino and ethoxycarbonyl groups in 362 results in formation of an additional ring. This domino process provides efficiently 4/7-indolo[2,3-i ]l,2,3-triazolo[l,5- ]pyrimidines 363 in 70-80% yield (Scheme 57) <2006TL2187>. 

A method frequently used to determine aromatic amines in water-soluble dyes involves their extraction with chloroform, followed by diazotization of amines and coupling of diazonium salts with a reagent R-salt (disodium-3-hydroxy-naphthalene-2,7-disulfonate) or pyrazolone T (4,5-dihydro-5-oxo-l-(4-sulfophenyl-)l/7-pyrazole-3-carboxylic acid). The separated products are detected by UV-VIS spectrophotometry or fluorescence (210-212). 

Nitrosonium ion (NO+) is the electrophilic species formed from nitrous acid media, which is responsible for such reactions as diazotization of amines. Nitrosonium ion has... 

In the Woodward synthesis of prostaglandin (621, intermediate 172 formed in situ from the corresponding amine was smoothly transformed into bicyclic aldehyde 173. Seebach and co-workers (63) have also observed several stereospecific rearrangements using the same reaction. For example, diazotization of amine 174 gave specifically the cis-cyclopentane 175 which was then epimerized into the more stable trans-cyclopentane 176. 

While the process at the cathode always ends finally in withdrawal of oxygen or in taking up of hydrogen, the number of possible reactions at the anode—aside from solution-phenomena, which are without interest here—is a much greater one. For, each ion which is capable of substituting can pass into the reactive state at the anode and produce reactions which cannot be numbered with the real oxidations. In the first place numerous substitutions can occur in difficultly oxidizable bodies, especially aromatic compounds, for instance the chlorination of phenols and phthale ins, nitration of acids, diazotizing of amines, etc. Substitution and oxidation processes often occur simultaneously, as in the electrolytic formation of iodoform from alcohol. 

Similar steric restrictions of a ring-opening gave substitution products 591, 594, 596, 598 and 600 from the diazotation of amines 589, 592 ", 59556,61.62,124 597 and... 

The diazotization of amines is somewhat troublesome and stock solutions cannot be stored for long because of their lack of stability. There was, therefore, a great demand for stabilized diazonium salts which, when dissolved in water, would immediately be ready for use. Such products are usually marketed under the name of Fast Salts such as Fast Red Salt RL, Fast Blue Salt BB, the Brentamine Fast Salts, etc. The earliest of these were the so-called anti-diazotates. 

Nitrite ion has been shown to be toxic in the human body and animals, since diazotization of amines present in the body can lead to carcinogenic N-nitroso compounds. Furthermore, nitrite oxidizes hemoglobin to methemoglobin which is incapable of binding oxygen. In contrast, nitrate itself is not toxic but is easily reduced to nitrite by microorganisms. 

The use of more effective protecting groups, N-demethylation, diazotization of amines derived from cyanide reduction, Grignard displacement of cyanide, all proved fruitless. Rapoport then returned to enamine 145 and, in keeping with Evans observations, found that both kinetic and thermodynamic protonation, to trans and cis immonium salts respectively, was possible (see also Scheme 14). However, attempted... 

Regitz diazo transfer reactions have been reviewed previously.1-3 The following two main routes have been known for the synthesis of diazo compounds (1) diazotization of amines, oximes, nitrosoamines, and hydrazones (2) transfer of the diazo function from tosyl or mesyl azides to active methylene compounds. 

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). 

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