Nitrous acid amides

In addition to General Reactions i and 2, all amides react with nitrous acid evolving nitrogen ... 

The evolution of nitrogen is not always entirely satisfactory as a test owing to the possible evolution of gaseous decomposition products of nitrous acid itself. The test may be performed as follows. To i ml. of chilled concentrated sodium nitrite solution add i ml. of dilute acetic acid. Allow any preliminary evolution of gas to subside, and then add the mixed solution to a cold aqueous solution (or suspension) of the amide note the brisk effervescence. 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

If primary or secondary amines are used, A/-substituted amides are formed. This reaction is called aminolysis. Hydra2ines yield the corresponding hydra2ides, which can then be treated with nitrous acid to form the a2ides used in the Curtius rearrangement. Hydroxylamines give hydroxamic acids. 

This vinylogous amide has been prepared in 70% yield to protect amino acid esters. It is cleaved by treatment with either aqueous bromine or nitrous acid (90% yield). ... 

They are converted by nitrous acid into the organic acid, and in the case of substituted amides into nitrosamides,... 

Substances of this type have hitherto received little attention. One of the reasons appears to be the limited possibilities of preparation. The only known method of preparation, described by Woolley et ai./ proceeds from the derivatives of 4-aminoimidazole-5-carboxylic acid. The amide of this acid (142) is treated with nitrous acid to yield 4-hydroxyimidazo [4,5-d]-i -triazine (2-azahypoxanthine) (143), the amidine (144) yielding the 4-amino derivative (2-azaadenine) (145) under the same conditions. 2-Azahypoxanthine was probably obtained in the same way earlier but was not identified. ... 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

Replacement of chlorine on the pendant benzoyl group by azide is apparently consistent with antiinflammatory activity. Acylation of indomethacin intermediate with p-nitrobenzoyl chloride leads to the corresponding amide (7). Saponification ( ) followed by reduction of the nitro group gives the amine 9. The diazonium salt (10) obtained on treatment with nitrous acid is then reacted with sodium azide there is thus obtained zidomethacin (11). 

The nitrosation of amides may also be carried out with nitrosyl chloride.2 Related methods of deamination of aliphatic amines are the triazene3 and nitrous acid methods4... 

These reactions involve a diazonium ion (see 12-47) and are much faster than ordinary hydrolysis for benzamide the nitrous acid reaction took place 2.5 x lo times faster than ordinary hydrolysis. Another procedure for difficult cases involves treatment with aqueous sodium peroxide. In still another method, the amide is treated with water and f-BuOK at room temperature. " The strong base removes the proton from 107, thus preventing the reaction marked k j. A kinetic study has been done on the alkaline hydrolyses of A-trifluoroacetyl aniline derivatives. Amide hydrolysis can also be catalyzed by nucleophiles (see p. 427). 

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... 

Reaction between secondary amines or amides and nitrous acid... 

As noted above, a convenient pathway to cinno-lines consists of intramolecular condensation of a diazonium group with a ketonic methyl group, or alternately with a double bond. The analogous reaction with an amide nitrogen leads to 1,2,3-benzotriazines, such as 198. Reaction of isatoic anhydride with N-aminomorpholine affords the hydrazide 196 then, treatment with nitrous acid yields initially the diazonium salt (197). Under the reaction conditions... 

While screening for p-lactam antibiotics stable to p-lactamases, a strain of Streptomyces lactamdurans was found to contain several such agents which have a 6-a-methoxy group whose electronic and steric properties protect the antibiotic from enzymatic attack. Cephamycin C (29a), one of these substances, is not of commercial value, but side chain exchange has led to much more potent materials. Of the various ways of effecting this transformation, one of the more direct is to react cephamycin C with nitrous acid so that the aliphatic diazo product (29b) decomposes by secondary amide participation giving cyclic iminoether 30. The imino ether moiety solvolyzes more readily than the p-lactam to produce 7-aminocephamycinic... 

A bacterial phosphatidylinositol specific phospholipase C (PI-PLC) had been available for many years before it was demonstrated to strip a number of membrane-bound proteins from eukaryotic cell surfaces [1], Such proteins are anchored by a PI moiety in which the 6 position of inositol is glycosidically linked to glucosamine, which in turn is bonded to a polymannan backbone (Fig. 3-10). The polysaccharide chain is joined to the carboxyl terminal of the anchored protein via amide linkage to ethanolamine phosphate. The presence of a free NH2 group in the glucosamine residue makes the structure labile to nitrous acid. Bacterial PI-PLC hydrolyzes the bond between DAG and phosphati-dylinositols, releasing the water-soluble protein polysac charide-inositol phosphate moiety. These proteins are tethered by glycosylphosphatidylinositol (GPI) anchors. 

Nitrosamines, which are the amides of nitrous acid, are more stable and are derived from secondary amines with nitrous acid. iV-nitrosamides are substances which have a carbonyl group attached to a nitrogen-bearing NO group, e.g. iV-nitrosamides, iV-nitrosocarbamates and /V-nitrosoLireas see Figure 10. 

Photolytic. Dimethylnitramine, nitrous acid, formaldehyde, V.V-dimethylformamide and carbon monoxide were reported as photooxidation products of dimethylamine with NOx. An additional compound was tentatively identified as tetramethylhydrazine (Tuazon et al., 1978). In the atmosphere, dimethylamine reacts with OH radicals forming formaldehyde and/or amides (Atkinson et al, 1978). The rate constant for the reaction of dimethylamine and ozone in the atmosphere is 2.61 x 10 cmVmolecule-sec at 296 K (Atkinson and Carter, 1984). 

A mixture of concentrated sulfuric and nitric acids has been used for the A-nitration of amides and ureas. A, A -Dinitro-A,A -bis(2-hydroxyethyl)oxamide dinitrate (NENO) (11) is prepared from the action of mixed acid on A, A -bis(2-hydroxyethyl)oxamide (61), itself prepared from the condensation of diethyloxalate with two equivalents of ethanolamine. Niuo-sylsulfuric acid is an inhibitor of A-nitration and so nitrous acid should be rigorously excluded. The reaction of (61) with absolute nitric acid results in 6>-nitration of the hydroxy groups but no A-nitration, and consequently, (62) is isolated as the sole product. 

Its composition, C H7N04, was established in 1833 by Boutron-Charlard and Pelouze, and confirmed by Liebig. In 1848 Piria showed that aspartic acid was converted into malic acid by the action of nitrous acid, and he regarded aspartic acid and asparagine as the two amides of malic acid... 

---