Nitroso compounds substitution

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. 

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. 

Electrophilic nitrosation of the carbanion generated from the reaction of an organic base with a strong organic acid, such as a-hydrohexafluoroisobutyronitnle [2], a hydrohexafluoroisobutyric acid or its acid chloride [2], or a hydrotetra fluoroethanesulfonyl fluoride [4], yields the corresponding a-nitroso compound as the major product (equations 2 and 3) The a-hydrohexafluoroisobutyric acid or acid chloride reacts with excess trifluoroacetyl nitrite in dimethylformamide to afford the O substituted oxime [3] (equation 4)... 

Fluorinated heterodienophiles and heterodienes Diels-Alder reactions in which the dienophiles have perfluoroalkyl-substituted multiple bonds between carbon and a heteroatom are quite common Reported earlier were reactions of perfluoroketones, thiones, ketimines, thioesters, nitroso compounds, and nitriles [9] Examples of a-fluoroimines [107], co-hydroperfluorothioaldehydes [108], perfluorosulfines [109, IIO], and selenocarbonyidifluoride [III] (equations 89-92) have been reported recently... 

Trifluoromethyl-substitutedazimines are surprisingly stable compounds. They are accessible by 1,3-dipole metathesis from tnfluoromethyl-substituted azomethine imines and certain nitroso compounds [187, 188] On photolysis, an electrocyclic ring closure first gives the triaziridines, which are stable at room temperature. On heating above 80-100 C, a valence tautomenzation takes place and azimines are formed [189] (equation 43). 

Substituted amides are converted to NR -substituted amides by treatment with N2O4 to give an N-nitroso compound, followed by treatment of this with a primary amine R NH2. ° Lactams can be converted to ring-expanded lactams if a side chain... 

When secondary amines are treated with nitrous acid, N-nitroso compounds (also called nitrosamines) are formed. The reaction can be accomplished with dialkyl-, diaryl-, or alkylarylamines, and even with mono-N-substituted amides RCONHR -I-HONO RCON(NO)R. Tertiary amines have also been N-nitrosated, but in these cases one group cleaves, so that the product is the nitroso derivative of a secondary amine.The group that cleaves appears as an aldehyde or... 

From the point of view of the synthetic organic chemist, the importance of aromatic thallation, and the remarkable degree of orientation control which can be exercised over this process, lies in the ease with which the resulting ArTlXj compounds can be converted into substituted aromatic derivatives in which the new substituent group has entered the ring at the position to which thallium was originally attached. Syntheses of phenols, nitroso compounds, biaryls, aromatic nitriles, thiophenols, and deuterated aromatic compounds have all been achieved these results are summarized briefly below. 

Under appropriate conditions, they are readily N-nitrosated. The authors tentatively concluded that the major contribution of N-substituted amides, if they were present in foods, could be as precursors of N-nitroso compounds formed by vivo N-nitrosation reactions ... 

The N-diazeniumdiolates are quite photosensitive. Studies of various 02-substi-tuted compounds, both alkyl and aryl, revealed a primary photochemical reaction involving cleavage of the N=N bond to yield a nitrosoamine and an O-substituted nitrene which rearranges to a C-nitroso compound (Scheme 3.31), the latter is often isolated as the oxime [224]. 

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

In Table 13 the ionization potentials of some more C-nitroso compounds are collected. The spectrum of monomeric t-nitrosobutane126 exhibits a well separated band at 9.05 eV. The following ionizations show maxima at 11.85 and 12.46 eV. The spectrum is dominated by a strong composite band from 12.9-14.5 eV. The spectrum can be assigned by comparison with nitrosomethane. The substitution of Me by t-Bu lowers the n ionization energy of the nitroso group by 0.7 eV, whereas the n+ and it ionization energies are lowered by 1.8 and 1.7 eV, respectively. 

The H-NMR spectra of amino, nitro and nitroso compounds have been reviewed16,17, and the effects of these substituents on the proton chemical shifts have been investigated16. Table 4 gives these substituent effects for mono-substituted benzenes. 

The diastereomeric 2-cli loro-2-nitroso-p-menthanc and 3-chloro-3-nitroso-p-menthane (267) epimerize during photolysis143 (equation 119) and can concurrently give the nitrox-ide 269 as detected by ESR spectrometry, which confirms the mechanism for the photolysis of geminally substituted nitroso compounds (equations 120 and 121). 

The first examples of this reaction (which was reviewed several times85), i.e. the addition of nitrosoarenes to 2,3-dimethylbutadiene to give 2-aryl-3,6-dihydro-2//-l,2-oxazines (equation 94), were reported in 194786. In general, the addition of nitroso compounds to 1,3-dienes to form dihydro-1,2-oxazines is only observed if the nitroso compound is activated by an electron-withdrawing group87. Kinetic studies of the reaction of cyclohexa-1,3-diene with para-substituted nitrosobenzenes (equation 95) show the accelerating effect of such groups (Hammett constant p = +2.57)88. 

Preparative scale reduction of nitramines and nitrosamines in acid solution is a convenient route to substituted hydrazines. Early workers used a cathode of tinned copper [120], More recently mercury has been employed as cathode material, although tin would probably be equally suitable. Nitrosamines are conveniently reduced in dilute hydrochloric acid and evaporation of the electrolyte at the end of the reaction affords the hydrazine hydrochloride [121]. Some nitroso compounds are unstable to these acidic conditions. In the case of N-nitrosoindoles, this problem has been overcome in an ingenious manner [122]. The nitroso compound and aqueous sulphuric acid are mixed just prior to reaction and then forced through a porous cathode of bronze coated with mercury at such a rate that the reduction is completed in one pass through the cathode. Other workers have overcome the instability of N-benzyl-N-nitrosoanthraniiic acid towards acid by working in an acetate buffer at below room temperature [123],... 

The following types of dipolarophiles have been used successfully to synthesize five-membered heterocycles containing three heteroatoms by [3 + 2]-cycloaddition of thiocarbonyl ylides azo compounds, nitroso compounds, sulfur dioxide, and Al-sulfiny-lamines. As was reported by Huisgen and co-workers (91), azodicarboxylates were noted to be superior dipolarophiles in reactions with thiocarbonyl ylides. Differently substituted l,3,4-thiadiazolidine-3,4-dicarboxylates of type 132 have been prepared using aromatic and aliphatic thioketone (5)-methylides (172). Bicyclic products (133) were also obtained using A-phenyl l,2,4-triazoline-3,5-dione (173,174). 

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 ). 

While the condensation of amines with nitroso compounds appears to have wide applicability in the benzene series, it seems to lead to complex dye molecules in the naphthalene series. A method has been developed using a somewhat complex reaction between thionylamines and substituted hydroxylamines which does produce azo compounds derived from naphthalenes. This synthesis is of particular interest because it helped to settle the question whether true naphthylazo compounds with hydroxyl groups could exist [36]. 

---