Nitroso formate, substituted

Inhibition of Nitrosamine Formation. Nitrites can react with secondary amines and A/-substituted amides under the acidic conditions of the stomach to form /V-nitrosamines and A/-nitrosamides. These compounds are collectively called N-nitroso compounds. There is strong circumstantial evidence that in vivo A/-nitroso compounds production contributes to the etiology of cancer of the stomach (135,136), esophagus (136,137), and nasopharynx (136,138). Ascorbic acid consumption is negatively correlated with the incidence of these cancers, due to ascorbic acid inhibition of in vivo A/-nitroso compound formation (139). The concentration of A/-nitroso compounds formed in the stomach depends on the nitrate and nitrite intake. 

A solvent-free synthesis of substituted spiroindolinonaphth[2,l-fo][l,4]oxazines through condensation of 2-methylene-l,3,3-trimethylindoline derivatives with 1-nitroso-2-naphthol under microwave irradiation has been described by Fedorova and colleagues (Scheme 6.263) [453], In a typical reaction, an equimolar mixture of the two starting materials was irradiated at 65-110 °C for 15 min to produce the desired spiroindolinonaphth[2,l-fo][l,4]oxazines, which are useful as photochromic compounds. In a related procedure, addition of morpholine to the reaction mixture led to the formation of the corresponding 6 -amino-functionalized spiroindolino-naphth[2,l-fo][l,4]oxazines, which exhibit a strong hypsochromic color shift (not shown) [453]. 

Scheme 7.4 Nucleophilic substitution of a C-acyl nitroso compound with nitroxyl formation.

The bimolecular reduction of nitro compounds is believed to involve reduction of some of the starting material to a nitroso compound and another portion to either a substituted hydroxylamine or an amine. These intermediates, in turn, condense to form the azo compound. The exact mechanism of the reaction requires critical study. On the one hand, reducing conditions are always on the alkaline side to prevent the benzidine rearrangement of an intermediate hydrazo compound under acidic conditions, yet it is difficult to visualize the formation of hydrazo compounds by the indicated condensation. As a practical matter, this method is of value only if symmetrically substituted azo compounds are desired. 

A convenient synthetic procedure for the preparation of azo compounds, particularly unsymmetrically substituted ones, involves the reaction of aromatic nitroso compounds with aromatic amines [31a, b]. The reaction is of particular interest because the replacement of the amine by the corresponding hydroxylamine leads to the formation of the related azoxy compounds (see Chapter 15, Azoxy Compounds ). 

Historically this reaction developed from the assumption that the formation of azoxy compounds by the reduction of aromatic nitro compounds probably involved the intermediate formation of C-nitroso compounds and hydroxylamines. In the all-aliphatic series, this reaction appears to be quite general. Symmetrically and unsymmetrically substituted azoxy compounds have been prepared by it, the only major problems being the usual ones of developing procedures that afford good yields and of determining the exact position of the azoxy oxygen in unsymmetrically substituted products. 

Typical primary amines which undergo such nitrosation are m-toluidine, p-xylidine, m-anisidine, 2-amino-4-methoxytoluene, 3-amino-4-methoxy-toluene, m-aminophenol, a-naphthylamine, l-naphthylamine-2-, -6-, -7-, and -8-monosulfonic acids, and l-naphthylamine-4-monosulfonic acid (which reacts with displacement of the sulfonic acid group). The secondary amines derived from these primary amines also can be nitrosated directly (i.e., without the intermediate formation of an JV-nitroso compound which needs to be subjected to the Fischer-Hepp rearrangement). The entering nitroso group appears to substitute exclusively in the para position. 

There appears to have been no systematic study, at least in recent years, of the nitrosation of substituted hydrazines. Work at the beginning of the century indicates that the nitrosation of primary hydrazines may result in the intermediate formation of nitroso compounds, but that these compounds subsequently react further, in the presence of nitrous acid, to give a variety of products. 1-Benzyl-1-nitrosohydrazine evidently has been prepared and subsequently benzoylated. The resultant A-nitrosohydrazide apparently is reasonably stable [61]. More recently, A-nitroso-A-alkylhydrazides have been prepared by ring cleavage of compounds such as A-benzamidopiperidine and A-benzamidopyrrolidine [62]. This method, however, does not appear to have very general applicability. 

Nitrosation of parent,214 2-substituted166,202 or 4,5,6,7-substituted pyra-zolo[l,5-a]pyridines220 occurred in the 3-position. Formation of 2-alkyl-3-nitroso analogs was also achieved by displacement of a 3-acyl group.218... 

The photochemistry of certain A-substituted heterocycles has also been studied. As part of a continuing investigation of the photolysis of A-nitroso compounds in solution, the conversion of A-nitroso-3-azabicyclo[3.2.2]nonane (65) into the oxime (66) by photolysis in the presence of acid was reported.58 N-Nitrosopyrrolidine is similarly transformed. The mechanism of this reaction is said58 to involve elimination of NOH with the formation of an imine as intermediate, and, in fact, in the photolysis of 2-ethyl-A-nitrosopiperidine (67), the tetrahydropyridine (68) is the major product. This mechanism certainly does not operate in the photolysis of iV-nitroso-2-azacyclo-octanone, which can be rationalized on the basis of an intramolecular hydrogen transfer [Eq. (16)].59 Acyclic iV-nitrosoamides behave in a similar fashion to IV-nitrosoamines.60... 

A third pathway for oxime formation is given by tautomerization of nitroso compounds possessing an a-hydrogen (equation 9). Such a process involves an intramolecular redox reaction, in which the nitrogen undergoes a formal two-electron reduction, while the a-carbon is oxidized. Kinetic analysis of this conversion, as performed with a set of a-substituted 2-nitroso-l-phenylethane compounds, has revealed sensitivity toward both the bulkiness of the substituents and the initial concentration of the nitroso dimers128. For instance, tautomerization of 2-nitroso-l-phenylpropane to 28 has been proposed to play a role in the metabolism of methamphetamine by fortified rat liver tissue129. 

Secondary aromatic amines under these conditions form initially the AT-nitroso derivative (see notes on the purification of secondary amines in Expt 6.56), which when treated with hydrogen chloride in anhydrous ethanol-ether solution rearranges to the nuclear substituted nitrosoamine (eg.. p-nitroso-AT-methylaniline, cognate preparation in Expt 6.62). This rearrangement proceeds via the intermediate formation of the electrophilic nitrosyl chloride ... 

Functionalization of the carbon radical resulting from cyclization of an aminium radical is an important step for synthetic chemists in order to obtain the desired product directly or to provide a handle for further transformations. Radical reactions of A-chloroalkenylamines (Section III,B) lead to /3-chloro pyrrolidines, which are prone to rearrangement to give piperidines. Reactions of N-nitroso alkenylamines lead to 8-nitroso pyrrolidines and, if an a-hydrogen is present, ultimately to oximes of aldehydes or ketones. Advantages of the latter transformation are the formation of stable substituted pyrrolidines and the utility of the oxime moiety in regard to further transformations. 

The oxidation of oximes by lead(IV) acetate, chlorine and other oxidants results in the formation of a-substituted nitroso compounds R R C(X)NO by attack of the oxidant at carbon. This is also the reaction commonly observ with dinitrogen tetroxide (the Ponzio reaction), the products being gem-... 

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