Amides A-nitroso

Other compounds with nitrogen-nitrogen bonds have been used instead of diazonium salts. Among these are A-nitroso amides [ArN(NO)COR], triazenes, " and azo compounds. Still another method involves treatment of an aromatic primary amine directly with an alkyl nitrite in an aromatic substrate as solvent. " ... 

The aiyl radical thus formed attacks the substrate to give the intermediate 42 (see p. 940), from which the radical 41 abstracts hydrogen to give the product, 43. A -Nitroso amides probably rearrange to A -acyloxy compounds (44), which cleave to give aryl radicals. " There is evidence that the reaction with alkyl nitrites also involves attack by aryl radicals. ... 

The N-N bond of A-nitroso amides is also easily cleaved by hydrochloric acid.161... 

This problem is not encountered in the thermal rearrangement of N-nitroso amides (7.10, R = alkyl). Aliphatic N-nitroso amides were first studied by von Pechmann (1898 a). The rearrangement was originally investigated and elucidated for aromatic A-nitroso amides by Huisgen and others (see summary by Zollinger, 1994, Sect. 6.7.5). 

Huisgen s work clearly showed that, in the rearrangement of the A-nitroso amides, the (jE )-diazo ester (7.11) is formed. Ionization of (7.11) leads to an ion pair (7.12), in which the distance between the C-atom adjacent to the diazonio group and the carboxylate group is greater than in the ion pair of the same stoichiometry, but formed by addition of a carboxylic acid to a diazoalkane (7.14). For obvious reasons, the carboxylate anion formed in such a protonation of a diazoalkane in an aprotic solvent is closer to the C-atom to be protonated. We will see in Section 7.3 that this hypothesis is consistent with different product ratios of dediazoniations of diazonium-carboxylate ion pairs originating from these two routes of formation. 

Instead of A-nitroso amides (7.10, R = alkyl or aryl), A-nitroso carbamates (7.10, R = OR") and A-nitroso ureas (7.10, R = NHR) can also be used (Kirmse and Wachtershauser, 1967 Hecht and Kozarich, 1973). More recently, Kirmse s group (Kirmse and Rode, 1986 Kirmse et al., 1986 a) demonstrated that A-nitroso carbamates are preferable to A-nitroso amides because of higher yields in the nitrosa-tion step. In the synthesis of A-[l-(3-hydroxypropyl)cyclopropyl] acetamide (7.17) Kirmse and Rode (1987 b) found that primary nitrosation takes place at the hydroxy group, and N-nitrosation was achieved only after complete O-nitrosation. 

Recently, White et al. (1992 a) showed that A-nitroso sulfamates (7.18), a class of compounds related to A-nitroso amides, can be used for the generation of diazonium ions in aqueous buffers at pH 2, i. e., in an acidity range where direct nitrosation of aliphatic amines is very slow. 

In a second paper, Streitwieser and Schaeffer (1957 b) used the same sample of [l- H]butylamine for the A nitroso amide method of deamination in acetic acid and found complete racemization. They rationalized this result by assuming the formation of 1-diazobutane as an intermediate, as shown in (7-15). Although a repetition of this process, but using the NMR method for stereochemical analysis, is not likely to give a substantially different result, it would be welcome for clarification. 

Before we close this section, it should be mentioned that rhodium catalysts were added by Godfrey and Ganem (1990) to solutions of A-nitroso amides and they observed that the same products were obtained as with diazo compounds. This is, of course, not surprising, as diazo compounds are intermediates in the decomposition of A-nitroso amides. Yet, it is remarkable that, to the best of our knowledge, this method has not been investigated more frequently. 

Diazopenicillin (32 x) has been shown to be a useful intermediate for the synthesis of other 6-substituted penicillins, but its method of preparation has suffered from low yields. An improved procedure in which A-nitroso-amide (33 v) is treated with pyridine in refluxing methylene chloride afforded (32 v) as a crystalline solid in 72% yield. The corresponding 7-diazo-cephalosporins (34)... 

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 method for the preparation of olefins from primary amines is shown in equation 120. Treatment of 2-(4-bromophenyl)ethylamine (358) with acetic acid, acetic anhydride and sodium nitrite generates the nitroso amide 359, which decomposes to 4-bromostyrene in the presence of rhodium(II) acetate. The procedure is thus a mild, non-basic alternative to the classical Hofmann elimination of amines396,397. 

Nitric acid-acetic anhydride mixtures give poor yields for the nitration of amides with groups that hinder the amide nitrogen against electrophilic attack. The use of higher temperatures in these reactions leads to variable amounts of the A-nitroso compound as a by-product. ... 

Since acetic acid and acetic anhydride mixtures are excellent solvents for amides derived from primary carbinamines and cyclohexylamines, A-nitroso derivatives can be prepared in this solvent medium with sodium nitrite. The method appears to be somewhat more rapid than that carried in an aqueous medium, but fails when amides derived from secondary carbinamines are to be nitrosated. As the reaction medium is one which will also acetylate primary amines, appropriate amines may be dissolved in the reaction medium and, in turn, acetylated and nitrosated without the isolation of the intermediate amide. 

For a report of formation of about 15% ortho product in the case of N,N-diaryl-N-nitroso amides, sec Titova Arinich Gorelik /. Org. Chem. USSR 1986, 22, 1407. 

The rotational barriers of A-nitroso-, A-formyl and A-(A,A-dimethylcarbamoyl)-azetidines, compared with those of analogous acyclic amides, suggest that amide conjugation is weaker when the nitrogen is part of an azetidine ring (87KGS912). 

Secondary amides give A-nitroso compounds with nitrous acid, whereas tertiary amides do not react ... 

Nylon, nitrosated with dinitrogen trioxide according to Belg. Pat. 606 944 and stored cold, exploded on being allowed to warm to ambient temperature. The iV-nitroso nylon would be similar in structure to A-nitroso-A-alky I amides, some of which are thermally unstable. Nylon components should therefore be excluded from contact with nitrosating agents. 

The 1,3 dipole diazomethane is a mild reagent to furnish methyl esters (see Chapter 13), but it has some disadvantages, too it is volatile, toxic and furthermore explosive. For this reason it has to be prepared by reaction of KOH with A-methyl-A-nitroso-para-toluenesulfon-amide (carcinogenic ) or in situ Another simple method to protect the COOH functionality of the neuraminic acid is the esterification with methanol as solvent and reactand under H " catalysis e. g. ion exchanger. 

N-oxidation can occur in a number of ways to give either hydroxylamines from primary and secondary amines [Eqs. (11) and (12)], hydroxamic acids from amides, or N-oxides from tertiary amines [Eq. (13)]. The enzyme systems involved are either cytochrome P450 or a flavoprotein oxygenase. Hydroxylamines may be further oxidized to a nitro compound via a nitroso intermediate [Eq. (11)]. Oximes can be formed by rearrangement of the nitroso intermediate or N-hydroxylation of an imine, that could in turn be derived by dehydration of a hydroxylamine [Eq. (11)]. N-Oxides may be formed from both tertiary arylamines and alkylamines and from nitrogen in heterocyclic aromatic systems, such as a pyridine ring. 

Several different methods have been employed for the preparation of diazo(trimethylsilyl)meth-ane (1). At present, the best synthetic method seems to be the diazo transfer reaction between diphenylphosphoryl azide and (trimethylsilyl)methylmagnesium chloride.However, the product often contains (chloromethyl)trimethylsilane and hexamethyldisiloxane as impurities. This method can also be employed for the synthesis of diazo(triethylsilyl)methane and diazo(di-ethylmethylsilyl)methane. The diazo transfer reaction can also be carried out with (trimethyl-silyl)methyllithium and tosyl azide. Other methods are the silylation of diazomethane with (trimethylsilyl)trifluoromethanesulfonate or chloro(trimethyl)silane and the base-induced cleavage of A-nitroso-A-[(trimethylsilyl)methyl]urea or the related carbamate or acet-amide.2° =... 

Analoge Verfahren existieren fur sek. Amide. Hierzu sind u. a. die Nitrosierung mit Nitro-sylchlorid413 oder Natriumnitrit414 in Acetanhydrid oder Tetrachlormethan zu zahlen. Die primar gebildeten N-Nitroso-amide zerfallen thermisch in die entsprechenden Carbonsauren. 

Extensive preparative work was done in order to introduce novel substituents into the acid function of Mitozolomide (20) <90Jmci393>. Two approaches proved to be particularly successful nitrosation of the acid amide group to an A-nitroso derivative (21) followed by hydrolysis to the free acid (22) or preparation of the acid chloride (23) first and its alcoholysis to the ester (24), which proved to react with amines selectively at the acid function without any decomposition of the ring system (Scheme 3). 

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