Primary nitrosamine

Attempted diazotization in dilute acid sometimes yields primary nitroso compounds. Reactions of 3- and 5-amino-1,2,4-thiadiazoles with sodium nitrite and acid give primary nitrosamines (e.g. 432->433) (65AHC(5)n9) which can be related to the secondary nitrosamines (434) prepared in the normal way. 1-Substituted 5-aminotetrazoles with nitrous acid give stable primary nitrosamines (435). Primary nitrosamines have been isolated in the imidazole series. 

Primary amines react readily with nitrosating agents (Scheme 3.1) to provide deamination products. The intermediates, primary nitrosamines (RNHNO), are not stable therefore after a series of rapid reactions, they give rise to the diazonium ion (RN2+), and then decompose to the final products. The reactions of secondary amines can stop at the nitrosamine stage, since no a-hydrogen atoms are available for the necessary proton transfer reactions, which lead to diazonium ion formation. 

Oxidation, by chromic-acetic acid, of the hydroxylamine 272 yields the azoxy-thiadiazole 276 quantitatively, presumably via a primary nitrosamine the interaction of the hydroxylamine (272) with suitable nitrosamines does indeed afford mixed azoxy-thiadiazoles (277), but their exact structure is not known. Alkaline hydrolysis of s-azoxy-thiadiazole (276) yields the 1,2,4-thiadiazole diazotate 278 and hydroxy(or alkoxy)-1,2,4-thiadiazole 279, depending on the hydrolytic reagent employed170 (see also ref. 190). 

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. 

Nitrosamines are not carcinogenic at the point of application. They require bioactivation. One possible mechanism of biotransformation is by enzymatic transformation to a carbonium ion. Activation is known to proceed first by hydroxylation of an a-carbon. The resulting hydroxyalkyl moiety is eliminated as an aldehyde, and an unstable primary nitrosamine is formed. The unstable nitrosamine ultimately tautomerizes to a carbonium ion. The highly reactive carbonium ion readily alkylates with the nearby cellular macromolecules. Cancer and mutagenicity develop when reactive nitrosamine metabolites alkylate to genetic macromolecules. 

Primary amino groups on imidazole react with nitrous acid to give diazonium salts by way of primary nitrosamines. These salts can sometimes be isolated and converted into stable diazo anhydrides if the imidazole has a free NH group. Reviews of diazoazole chemistry have appeared... 

It was proposed that nitrosation of the exocyclic amide group resulted in a primary nitrosamine ... 

Desamination of guanosine, cytosine, and adenine is mediated in vivo primarily by the nitrosative chemistry of N2O3 (Wink et al. 1991, Nguyen et al. 1992). Nitrosation of an exocydic amine group has been proposed to lead to the formation of a primary nitrosamine, followed by rapid deamination which culminates in the formation of an hydroxyl group. 

---