Nitroso compounds reaction with active methylene groups

Reaction of nitroso compounds with active methylene groups to give imines [46a, b]. 

Although not particularly well known, nitrosoimidazoles appear to be quite stable compounds. The nitroso function can be reduced to amino, or oxidized to nitro. When 5-nitroso-2,4-diphenylimidazole is subjected to dropwise treatment with phenylhydrazine there is some reduction, but ring modification with the formation of the oxadiazole (224) accompanies this reaction (Scheme 123) (60G831). The nitroso function is able to take part in condensation reactions with compounds which possess active methylene groups, and related species (B-76MI40701). 

The reaction of 2-amino-3-nitrosopyridines with compounds containing an activated methylene group permits unambiguous synthesis of various derivatives of pyrido[2,3-b]pyrazine. For example, the pyridine 58 reacts in the presence of sodium ethoxide with a variety of arylacetonitriles and cyanoacetic acid derivatives to provide various 2-substituted 3-amino compounds (59). " " Diethyl malonate reacts similarly to give the 2-carboxylic acid 60, its ester being presumably hydrolyzed in the alkaline reaction conditions. Ethyl acetoacetate yields the 2-acetyl-3-oxo compound 61, and acetylacetone ° provides the 2-acetyl-3-methyl compound 62. The latter condensation proceeds poorly in ethanolic sodium ethoxide, but heating the nitroso compound with acetylacetone under reflux in pyridine gives a 59% yield of the product 62. °... 

In certain condensation reactions hydrogen may be replaced by oxygen, with interchange of the oxidation states of the carbon atoms that are to be bonded to one another. In such cases it is particularly nitroso compounds and derivatives of nitrous acid that serve as oxidant with active methylene groups they form Schiff bases or oximes, which afford the oxo compound on hydrolysis. 

Bromination of 2,3-dibenzylquinoxaline with excess of N-bromosuccinimide in carbon tetrachloride yields a mixture of meso- and d/-2,3-bis(a-bromobenzyl)quinoxalines. When 2,3-dimethylquinoxaline is treated in pyridine solution with powdered iodine, the bispyridinium iodide 37 is formed. Reaction with p-nitroso-iV,N-dimethylaniline gives the bisnitrone 38 which on acid hydrolysis yields quinoxaline-2,3-dicarboxaldehyde (40). The activated methylene groups of compound 37 condense with diacetyl in the presence of piperidine to give the phenazine derivative 39. 

The nitrosation of aliphatic carbon atoms, particularly of carbon atoms activated by adjacent carbonyl, carboxyl, nitrile, or nitro groups, has been reviewed in great detail [2]. Judging from this review, with few exceptions, nitrosation of active methylene compounds leads to the formation of oximes (unfortunately termed isonitroso compounds in the older literature). The few exceptional cases cited in which true nitroso compounds (or their dimers) were formed involved tertiary carbon atoms in which no hydrogen atoms were available to permit tautomerism to the oxime or involved a reaction which was carried out under neither acidic nor basic conditions. 

The methylene carbon atom in a condensed 4-thiazolidinone flanked by a sulfur atom and a carbonyl group possesses enhanced nucleophilic activity and attacks an electrophilic center with ease. If the structure permits, the reaction product loses a molecule of water, and an unsaturated derivative is formed. The reaction is carried out in the presence of a base which abstracts a methylene proton. It is the anion thus formed that attacks the electrophilic center. Generally, the anion condenses with aromatic aldehydes, nitroso compounds, aryidiazonium salts, and ethyl orthoformate, as well as undergoing Vilsmeier-Haack and Mannich reactions. 

The nucleophilic attack on the nitrogen atom of a nitroso group is the limiting stage of condensation reactions of nitroso compounds with amines, methylene-active, and organomagnesium compounds, of Ehrlich-Sachs, Fischer-Hepp, Burton, and other reaction [161,162]. 

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