A-nitroso derivatives

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCl"). Since many V-nitroso compounds are carcinogens, and because some racemization and cyclodehydration of V-nitroso derivatives of V-alkyl amino acids occur during peptide syntheses, V-nitroso derivatives are of limited value as protective groups. 

As discussed in the three preceding sections, the key intermediate in diazotizations is the A-nitroso derivative of the primary amine, the formation of which is usually the rate-determining step of diazotization. The subsequent steps are faster and therefore not easily accessible to study. The sequence of protonation, deprotonation, protonation, and dehydration in Scheme 3-36 seems to be the most reasonable mechanism. 

Carbamate pesticides can easily be converted to A-nitroso derivatives in the presence of sodium nitrite under acidic conditions. The A-nitroso form of carbofuran could possibly be formed in the human stomach (Nelson et al. 1981). Since carbofuran is used routinely on a variety of crops and nitrite is a common component of the human diet and present in human saliva, nitrosation of carbamates under conditions simulating those in the human stomach is possible. Lijinsky and Schmal (1978) tested nitrosocarbofuran and five other nitrosated carbamate pesticides for carcinogenicity in rats. Nitrosocarbofuran, at 16.5 mg/kg BW administered orally once weekly for 23 weeks, was the most toxic compound tested and caused the death of several animals by liver damage early in the experiment. Among survivors, nitrosocarbofuran was the most carcinogenic,... 

The toxicity of dapsone is due to the cytochrome P-450-catalyzed oxygenation leading to iV-hydroxydapsone. This major metabolite enters red cells and is co-oxidized with oxyhemoglobin to generate a nitroso derivative and methemoglobin148. 

Diazocines are eight-membered heterocycles containing two nitrogen atoms. The A-nitro and A-nitroso derivatives of 1,5-diazocines are energetic materials with potential for use in high-energy propellants. 

For example, it reacts with ketone to yield a nitroso derivative ... 

Propylene oxide undergoes electrophilic addition, giving a nitroso derivative, CH3CH(—0N=0)CH2C1 ... 

Meso-ionic 3-alkyl-l,2,3,4-oxatriazol-5-ones (271) are obtained by the nitrosation of 1-alkyl semicarbazides, RNHNHCONHj. At low temperatures, the intermediate A-nitroso derivatives (272) can be isolated, which cyclize on heating. An alternative synthetic route is illustrated by the formation of meso-ionic 3-methyl-l,2,3,4-oxatriazol-5-one (271, R = Me) from A-nitroso-iV-methylhydrazine (273) and phosgene. ... 

Some unusual electrophiles are shown. Benzothiazines 219-221 were reacted with HNO2 to give the versatile A -nitroso derivatives 222-224 or with cyclopentenone/Af-bromosuccinimide (NBS) to give 225-227 (Scheme 24) <2003JME3670>. Dihydrothiazinedicarboxylic acid 228 was reacted with 2,2-dimethoxypropane to form bicyclic product 229 (Equation 18) <1968T2985>. 

This route to the a-nitroso derivatives of the 7r-deficient heterocycles has permitted an exploration of their chemistry. They are extremely reactive and condense readily with 1,3-dienes to give 3,6-dihydro-l,2-oxazines (e.g. 99), and with aromatic amines in the presence of acid to give azo compounds (Scheme 86). This latter reaction is particularly useful in view of the instability of the corresponding 2-pyridinediazonium salts referred to above, which limits conventional access. The a-nitroso heterocycles are oxidized by ozone or sodium hypochlorite to the a-nitro compounds (Scheme 86) (82JOC553). 

The thioamide function also provides the entry for the construction of a fused imidazole ring, though the sequence is somewhat more complex due to the need to form a new carbon-carbon bond. Reaction of the thioamide (18-1) with methylamine proceeds to give the corresponding amidine this is transformed into a good leaving group by conversion to the A-nitroso derivative (18-2) by treatment with nitrous... 

Although there are exceptions, which will be mentioned in the appropriate sections of this chapter, A-nitrosation is usually carried out on nitrogen compounds in which the nitrogen bears only one hydrogen. The A-nitroso derivatives frequently are thermally or photolytically unstable or both. Many of them have a corrosive action on the skin or on the mucous membranes, and some are said to be carcinogenic. Consequently all A-nitroso compounds must be handled with extreme caution. 

The stability of A-nitroso derivatives of aromatic amines varies over a wide range. This variation appears to be related to the substituents on the aromatic nucleus. Nitrosoamides also may decompose photolytically, particularly in an acid medium [39]. 

In certain cases, iV-nitroso derivatives of secondary amines have been used as a means of purifying amines [3]. In this procedure, A-nitroso derivatives of amines are prepared, isolated, and then reduced with stannous chloride and hydrochloric acid. Isolation of the amines from the reducing medium evidently produces compounds purer than those purified by more conventional means. 

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. 

The chemical reactions in the preparation appear to be as follows. (1) The alcohol is oxidized to acetaldehyde, and (2) the nitrous acid which is formed attacks the acetaldehyde to form a nitroso derivative which goes over to the more stable, tautomeric, isonitroso form. 

Allesandro and co-workers have also described analysis of indomethacin by formation of a nitroso derivative which has an ultraviolet absorption maximum at 317 nm(40). 

Imino-A-4-thiazoline (29) reacts with sodium nitrite to give a nitroso derivative (30) that decomposes on heating to the A-4-thiazoline-2-one (31) (Scheme 13) (29). 

Song et al. [11] developed a polarographic method for the determination of mefenamic acid in tablets, which was based on rapid nitrosation of mefenamic acid with sodium nitrite in acetic acid, and subsequent measurement of the A-nitroso derivative of mefenamic acid by linear-sweep polarography. The method is simple, sensitive, and specific, and was characterized by a detection limit of 2 x 10 7 mol/L. 

A review of the chemistry and biological actions of colchicine and its derivatives has been published.536 The 13C n.m.r. spectra of colchicine and its derivatives have been studied537-540 and the structure (119) has been determined for epoxycolchicine (prepared from colchicine by the action of water and sodium peroxide) by X-ray crystallographic methods 541 other n.m.r. studies have shown that the double-bond in dehydro-7-deacetamidocolchicine is placed as shown in (120), and not in the 6,7-position, as previously supposed.542 The treatment of deacetyl-colchicine with isocyanates affords the related substituted ureas, which can be converted into A-nitroso-derivatives by treatment with nitrous acid these have been evaluated as inhibitors of neoplasms and as virucides.543 /V-Demethylation and O-demethylation of A-methylcolchiceinamide by micro-organisms has been achieved.544... 

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