Nitroso compounds reductive alkylation

In reaction of aliphatic nitro compounds with alkyl radicals 6 7 generated from ethers or alcohols aminyloxides 69b could be detected79. Moreover dialkylaminyl-oxides 74b are formed, 67 being trapped from the corresponding nitroso compound. Reduction of nitro compound to nitroso compound probably occurs by electron transfer from alkyl radical 67 to nitro compound, subsequent dissociation of the resulting complex 68b giving nitro anion radical which finally disproportionates. 

The N,]S -dialkyl-/)-PDAs are manufactured by reductively alkylating -PDA with ketones. Alternatively, these compounds can be prepared from the ketone and -lutroaruline with catalytic hydrogenation. The /V-alkyl-/V-aryl- -PDAs are made by reductively alkylating -nitro-, -nitroso-, or /)-aminodipheny1 amine with ketones. The AijAT-dialkyl- PDAs are made by condensing various anilines with hydroquinone in the presence of an acid catalyst (see Amines-aromatic,phenylenediamines). 

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. 

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). ... 

Reductive alkylations have been carried out successfully with compounds that are not carbonyls or amines, but which are transformed during the hydrogenation to suitable functions. Azides, azo, hydrazo, nitro and nitroso compounds, oximes, pyridines, and hydroxylamines serve as amines phenols, acetals, ketals, or hydrazones serve as carbonyls 6,7,8,9,12,17,24,41,42,58). Alkylations using masked functions have been successful at times when use of unmasked functions have failed (2). In a synthesis leading to methoxatin, a key... 

Reductive alkylation has also been carried out on nitro, nitroso, azo, and other compounds that are reduced in situ to primary or secondary amines. 

The field of reductive preparations for the formation of nitroso compounds has not yet been adequately explored. For example, only indirect evidence exists that the electrolytic reduction of f-nitroalkanes to tertiary alkyl-hydroxylamines proceeds by way of nitroso compounds. 

It is natural to presuppose that the reduction of nitro compounds should lead to the nitroso compounds, at least as an intermediate stage. Until quite recently, no reductive processes for the formation of nitrosoalkanes were known [3], More recently, some indirect evidence is said to show that, on electrolytic reduction of tertiary aliphatic nitro compounds, the final t-alkyl-hydroxylamines are produced by the intermediate formation of nitroso compounds which were not isolated [99]. 

The reduction of nitroso compounds in the presence of ketones can be used for the reductive alkylation of amines ... 

In the course of investigations involving the reaction of lithium triethylhydroborate with conjugated nitroalkenes (61),A -ethylamines (62) were consistently observed as by-products (equation 34). The intermediacy of nitroso compounds has been confirmed in this reaction which provides a useful method for the preparation of A -ethylated amine derivatives. These A -alkylated products are not produced when sterically demanding reagents, such as potassium tri-s-butylborohydride, are used. Apparently, the competition between reduction and alkylation of the nitroso group is sensitive to steric effects. 

Reductive alkylation has also been carried out on nitro, nitroso, azo, and other compounds that are reduced in situ to primary or secondary amines. Azo compounds react with aldehydes, in the presence of proline, and subsequent reduction with NaBH4 gives the chiral hydrazine derivative. ... 

This is an excellent and popular method but removal of the chiral auxiliary is rather difficult and must be carried out oxidatively to produce the aldehyde product 25A. The chiral auxiliary emerges as the IV-nitroso compound 23 and this can be recycled. An alternative is alkylation (Mel) and acidic hydrolysis. Reductive removal gives the amine 25B and an intermediate 26 in the synthesis of SAMR... 

It is often possible to replace a primary amine in a reductive alkylation by a nitrogen compound such as a nitro or nitroso compound or nitrile that can be converted into the primary amine by the reduction. For example, A-alkyl-and A,iV-dialkyl-anilines can be prepared from nitrobenzene in a single operation.1010,1011 Directions for the preparation of A-alkylarylamines from aromatic nitro compounds are given on page 555. 

Oxadiazinan-2-ones 300 are obtained from norephedrine in good yield via N-alkylation, nitrosation, reduction, and cyclization <2002JHC823, 1996JME3938>. The nitroso compounds 299 are reduced with lithium aluminium hydride and the intermediate hydrazine alcohols cyclized with carbonyldiimidazole to afford compounds 300 (Scheme 37). Similarly, l,3,4-oxadiazinan-2-one derivatives 302 are obtained by reaction of hydrazino alcohols 301 with diethylcarbonate and sodium hydride (Equation 50) <2004SC835>. 

A method for the preparation of unsymmetrical azoxy compounds involves the reaction of certain diimide dioxides with Grignard reagents [5]. This reaction has somewhat limited applicability because the diimide dioxides which were used were prepared by alkylation of organonitrosohydroxylamines, a class of compounds of which cupferron is perhaps the best-known example. The reaction is, in effect, a reduction of a diimide dioxide to an azoxy compound by use of a Grignard reagent. The overall process is represented by Procedure 2-3. Since the starting materials are, in effect, unsymmetrically substituted nitroso dimers, extension of the reaction to nitroso dimers would be interesting. 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

Most syntheses of tertiary amino-3-pyrazolin-5-ones are based on an alkylation by one means or another of the primary or secondary amino analogs. In some cases simultaneous reduction of a nitroso or nitro compound or of a Schiff base and alkylation of the amine so formed is carried out. 4-Dimethylamino-3-pyrazolin-o-ones (amino-... 

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