Oxidation with Nitrous Acid

Secondary A -nitrosamines are frequently isolable and are formed reversibly from secondary amines and nitrous acid (HONO) and other nitrosating agents. 

Primary amines on reaction with nitrous acid undergo deamination to generate nitrogen (N2), alcohols, and alkenes. 

Diazomethane (CH2N2), which is toxic and known to explode in the presence of sharp objects or rough surfaces (Caution Do not work with ground glass flasks or boiling stones, etc.), is generally prepared and used as diethyl ether (ethyl ether. 

Reduction of groups attached to amines (aromatic rings and carbon-carbon double and triple bonds) can be effected by methods previously discussed. These include (a) catalytic hydrogenation with hydrogen gas (H2) over a metal catalyst such as platinum (Pt), nickel (Ni), or palladium (Pd) (Equation 10.37) and (b) dissolving metals such as sodium (Na) in an alcohol solvent/reactant (Equation 10.38). Some nitrogenous materials have been known to poison some catalysts and thus experimentation is often necessary. 

Hydrogenolysis (reduction with bond breaking) of benzylamines resulting in the formation of toluene and debenzylated amine is formally a reduction of the amine. Thus, as shown in Equation 10.39, treatment of A -benzyl-1,23,4-tetrahydroisoquinoline dissolved in ethanol with hydrogen (H2) gas at about 1 atm pressure in the presence of aqueous hydrochloric acid (HCl(aq)) and a platinum (Pt) catalyst, results in formation of the tetrahydroisoquinoUne base (present as is hydrochloric acid salt) and toluene. 

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The reaction of tertiary amine oxides with nitrous acid has also been shown to produce N-nitroso compounds. The mechanism for the amine oxides is similar to that for the tertiary amines (26). 

Phenoxazine and 3-acetoxyphenoxazine, as well as their 10-acetyl derivatives, when oxidized with nitrous acid at 5°, are converted into 3H-phenoxazin-3-ones.40... 

Aminopyrazine 1-oxide with nitrous acid in sulfuric acid on wanning and dilution with water (108, 547a), and also by treatment with potassium cuprous cyanide (838), has been shown to give 3-hydroxypyrazine 1-oxide. 2-Amino-3,5-dimethylpyrazine 1 -oxide with about 40% sodium hydroxide at reflux in a bath at 140° produced 2-hydroxy-3,5-dimethylpyrazine 1-oxide (524). 

On heating indigo blue with acetic anhydride, sodium acetate, and zinc powder, a diacetylindigo white is obtained. On oxidation with nitrous acid in presence of acetic acid, diacetylindigo blue is formed. This compound forms small glittering red crystals, soluble in benzene with a beautiful red colour. Its constitution is expressed by the formula ... 

As noted in Table 10.2 and in the footnote following Figure 7.3, a portion of the expanded Walden inversion involved treatment of (5)-(+)-2-aminosuccinic acid (aspartic acid) with NOBr (nitrosyl bromide) to produce (5)-(-)-2-bromosuccinic acid (Equation 10.49). We now know that NOBr acts as an oxidizing agent (see Section I [c]. Oxidation with Nitrous Acid and Schemes 10.18-10.20), which causes... 

Preparative Method prepared from the corresponding hydrazine by oxidation with nitrous acid. ... 

With nitrous acid it gives l-nitroso-2-naph-thol. It can also be chlorinated and sulphonated. Oxidized ultimately to phthalic acid on prolonged oxidation. 

Treatment of halomycin B (55) using nitrous acid yields rifamycin S (24) and the pyrroHdine (57) as shown in Figure 6. The halomycin B stmcture was confirmed by heating rifamycin O (23) and (57) in tetrahydrofiiran to yield halomycin B (20) which can also be converted to rifamycin S by electrochemical oxidation (213). Upon treatment with nitrous acid, halomycin A (54) yields rifamycin S along with the pyrroHdine (58). The stmcture for halomycin C (56) was deterrnined to be 20-hydroxy halomycin B based on mass spectral data (212). 

Amino groups are acetylated normally and are converted to hydroxy compounds with nitrous acid. Tlie 2,3-diamino [2,3-f>] derivative gives an imidazolo fused pyridopyrazine with acetic anhydride (75USP3898216). The oxidative removal of hydrazino groups has been used to give ring-unsubstituted derivatives (79JHC305). 

The purely chemical analogy involving nucleophilic attack and subsequent oxidation can be achieved by hydrogen peroxide, which converts pteridin-6-one into pteridine-6,7-dione (52JCS1620), and xanthopterin (4) into leucopterin (6) (39LA(539)179). Isoxanthopterin (5) reacts with nitrous acid to give pteridine-2,4,6,7-tetrone (44LA(555)146). 

Treatment of benzo derivatives with oxidizing agents leads to less predictable results. Thus, substituted 2,1-benzisoxazoles with nitrous acid or with CrOs/AcOH generated a variety of ring-opened products of higher oxidation state, the ratio of which depended on the amount of oxidant. These reactions are illustrated in Scheme 30. 

The importance of the configuration of the oxime is again demonstrated in the oxidative cyclization of o-aminobenzophenone oximes. The (Z)-oxime with nitrous acid produced 3-phenyl-l,2-benzisoxazole, while the (E)-oxime with similar treatment yielded ben-zotriazine N-oxides (27CB1736). 

The treatment of 3-amino-1,2,4-triazine 2-oxides 1 or 3-amino-1,2,4-benzotri-azine 1-oxides 29 with nitrous acid proceeds as a diazotization reaction, but the diazo compounds have never been isolated owing to the easy displacement of the di-azo group with nucleophiles. Thus the reaction of 3-amino-1,2,4-triazine 2-oxides 1 with sodium nitrite in hydrochloric or hydrobromic acids leads to the corresponding 3-halogen-1,2,4-tiiazine 2-oxides 119 or 3-bromo-l,2,4-benzotriazine 1-oxides 120 (77JOC546, 82JOC3886). 

Hey and Osbond converted (18) to 5 6-benzoquinoline (19) with copper powder in dilute acid solution, reaction probably going through the dihydro compound (20) which was oxidized by nitrous acid in the... 

Pyrrolobenzotriazine 43 was obtained by reaction of 42 with nitrous acid. Its demethylation with boron tribromide gave 44, whose oxidation... 

Several 5,6-disubstituted-3-azido[l,2,4]triazine-l-oxides 1021 were prepared (77JHC1221) by treatment of 1020 with nitrous acid. 3-Azido[l, 2,4]-triazine-2-oxide 1023 was prepared by reacting the corresponding 3-bromo derivative 1022 with either tetramethylguanidinium azide in chloroform or sodium azide in aqueous acetone. These azido derivatives were proven to exist in the open-chain form by H- and l3C-NMR and 1R spectra (77JHC1221) (Scheme 191). 

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