Nitrous acid, reaction with amides

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). 

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

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. 

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). ... 

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... 

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... 

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. 

Unsubstituted amides can be converted under very mild conditions into the corresponding carboxylic acids by treatment with nitrous acid. This reaction is useful when the usual hydrolysis conditions would affect other functions present, such as hemiacetals,214 as... 

Hydrazotc acid, HN,. ply.. = 4.72, and most of its covalent compounds (including its heavy metal salts) are explosive. It is formed (1) in 90% yield by reaction of sodium amide with nitrous oxide, (2) by reaction of hydraztntum ion with nitrous acid, (3) by oxidation of hydrazimum salts, (4) by reactio n of hydt azinium hydrate with nitrogen trichloride tin benzene solution). Hvdrazoic acid forms metal azides with the corresponding hydroxides and carbonates. It reacts with HC1 to give ammonium chlonde and nitrogen, with H2SO4 to form hydrazinium acid solfate, with benzene to form aniline, and it enters into a number of oxidation-reduction reactions. 

An indirect method of hydrolyzing some amides utilizes nitrous acid. Primary amides are converted easily to carboxylic acids by treatment with nitrous acid. These reactions are very similar to that which occurs between a primary amine and nitrous acid (Section 23-10) ... 

Reaction of lH-imidazole-4-carboxilic acid amide with nitrous acid leads to the diazonium salt (5-diazenyl-l-H-imidazole-4-carboxilic acid amide). Condensation of the diazonium salt with methylisocyanate leads to initial formation of unstable urea which cyclizes under the reaction condition to give 3,4-dihydro-3-methyl-4-oxoimidazo(5,l-d)-l,2,3,5-tetrazine-8-carboxamide (temozolomide). 

The reactivity of the amide function of phenanthridine-6-carbox-amide differs somewhat from that in the corresponding A-oxide. Although the former compound is smoothly converted to the amine under Hofmann conditions and forms the acid on treatment with nitrous acid, the amide A-oxide is virtually inert under the conditions of both reactions.290... 

---