Nitrosation with Nitrite Esters

Reaction time is extremely important in avoiding the side reaction illustrated in Eq. (1.1), where the nitroalkane product reacts with nitrite anion and any nitrite ester, formed as byproduct, to give a pseudonitrole. The reaction of sodium nitrite with alkyl halides is much faster than this competing nitrosation side reaction, even so, prompt work-up on reaction completion is essential for obtaining good yields. 

As indicated above, tertiary aromatic amines are directly C-nitrosated. The usual reagents are sodium nitrite and dilute hydrochloric acid, sodium nitrite and glacial acetic acid containing concentrated hydrochloric acid, and nitrite esters with hydrochloric acid [21a, 27]. While tertiary amines with such complex alkyl groups as found in A,A-di(3,5,5-trimethylhexyl)aniline are readily nitrosated [25], of the four A-butyl-A-methylaniline isomers, JV-r-butyl-A-methylaniline does not undergo the reaction, and even the nitroso compounds which did form were only unstable oils [27]. 

A variation of this procedure is the nitrosation of a phenol such as thymol in an alcohol solution with hydrochloric acid and sodium nitrite. This procedure is said to avoid the evolution of oxides of nitrogen, since it may involve the intermediate formation of ethyl nitrite as the nitrosating agent [31]. However, from the safety standpoint, the oxides of nitrogen and nitrite esters must be considered hazardous. 

The minor products frequendy formed in deaminations may result from such side reactions as reaction of the intermediate cation with nucleophiles, for example, acetate or chloride ions,49,30 present in low concentration. Nitrite ions can give rise to nitrite esters or ni-troalkanes 50,51 the former are probably hydrolyzed prior to or during processing of the products.52 Some alkenes have been reported to react with nitrous acid or related nitrosating agents.19,58 Enol ethers would be expected to be more nucleophilic than simple alkenes, and it has been found that D-glucal reacts with nitrous acid under the conditions of deamination.54... 

By interaction of 7-amino-8-oxo-3-vinyl-5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester with 4-bromoacetyl bromide was prepared 7-(4-bromo-3-oxo-butyrylamino)-8-oxo-3-vinyl-5-thia-l-azabicyclo (4.2.0)oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester. The active methylene group in that product was then nitrosated with sodium nitrite. The initial product spontaneously tautomerizes to afford 7-(4-bromo-2-hydroxyimino-3-oxo-butyrylamino)-8-oxo-3-vinyl-5-thia-l-azabicyclo(4.2.0) oct-2-ene-2-carboxylic acid 4-methoxyphenyl ester. By the reaction of that compound with thiourea and then with trifluoroacetic acid was obtained (6R,7R)-7-(2-(2-amino-4-thiazolyl)glyoxylamido)-8-oxo-3-vinyl-5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid sodium nitrite, (Z)-oxime (Cefdinir sodium nitrile). 

Nitrosation takes place in the benzenoid 5-position in pyrimidines with three strongly electron-donating groups, e.g., 0x0, thioxo, or amino groups. In disubstituted pyrimidines, the relative positions of the substituents are decisive for any reaction 4,6-diamino- and 4,6-dihydroxy-pyrimidines are 5-nitrosated whereas their 2,4-isomers fail to react. Nitrosation is brought about by nitrous acid or by nitrite esters. When the reaction is slow, an alkyl substituent may be nitrosated on the a-carbon the product is an oxime. An extensive review on nitrosopyrimidines is available [Pg.120]

Incompatible with strong oxidizers acids, water (slowly decomposes, forming amine and carbon disulfide). Reaction with nitrosating compounds (i.e., nitrogen oxides, nitrosyl chloride, nitrite esters, metal nitrates and nitroso compounds, etc.) can cause the formation of carcinogenic N-nitrosodiethylamine. 

Nitrones = -V-alkylidene amine N-oxides, 153 Nitrosyl chloride diazotization with, 312-313 nitrite esters from, 286 nitrosation of enol ethers, 268 Nocardicinic acid, 3-amino- (ANA 1,1-dimethylethyl ester synthesis, 161... 

As the proton release is often too slow under the acidic conditions used for the diazotization of aromatic amines, syntheses of aliphatic diazo compounds by this method are carried out without an excess of mineral acid. Usually, equimolar amounts of amine, HCl and NaN02, or amine and NOCl, are used. A better alternative is nitrosation with pentyl nitrite in the presence of up to 30% acetic acid, as found by Takamura et al. (1975). Yields higher than 60% were obtained with a-amino-substituted esters of some aliphatic carboxylic acids. 

Methods of formation of IV-nitrosamines from secondary amines have been reviewed. The most widely used reagent is sodium nitrite in an aqueous acidic medium others include nitrosyl chloride, nitrogen oxides and nitrite esters. Fremy s stdt (S03")2N0-] reacts with hydroxylamine in the presence of secondary amines to give A -nitrosamines, or, in the presence of an excess of hydroxylamine, tetrazenes RaNN sNNR . The nitrosating agent derived from hydroxylamine and Fremy s salt is suggested to be the anion (S03")2N0N0. ... 

In classical organic chemistry, nltrosamlnes were considered only as the reaction products of secondary amines with an acidified solution of a nitrite salt or ester. Today, it is recognized that nitrosamines can be produced from primary, secondary, and tertiary amines, and nltrosamides from secondary amides. Douglass et al. (34) have published a good review of nitrosamine formation. For the purposes of this presentation, it will suffice to say that amine and amide precursors for nitrosation reactions to form N-nitroso compounds are indeed ubiquitous in our food supply, environment, and par-... 

Recently, Kim and colleagues have described a new efficient method for the preparation of a-keto esters 48 via a free-radical acylation approach using (phenylsulfonyl) methoxycarbonyl oxime ether 46 as carbonyl equivalent radical acceptor (Scheme 28). The oxime 46 was conveniently prepared from readily available methylphenylsulfonyl acetate 44 by a two-step sequence (via oxime 45) as shown in Scheme 28. Nitrosation of 44 with isoamyl nitrite in the presence of sodium methoxide gave oxime 47 in 78% yield. 

A benzofuran ring replaces one of the benzene rings of the biphenyl moiety present in many of the sartans in the rather more complex drug saprisartan (80-10). It is of note, further, that the acidic proton is provided in this case by a trifluorosulfo-namide instead of the more common tetrazole ring. Construction of the imidazole fragment begins by nitrosation of the (3-ketoester (79-1) by means of sodium nitrite in acid to afford the oxime (79-2). Reaction with acetyl chloride leads to the ester (79-3). Reaction of this last intermediate with the iminoether from propionitrile then affords the imidazole (79-4). 

Predictably, nitrosation of 2-acetylpyrrole and pyrrole-2-carboxylic esters with alkyl nitrites or nitrous acid preferentially yields the relatively stable 4-nitroso derivatives, whilst 2,4-dialkyl- or -diaryl-pyrroles are nitrosated at the 5-position. Further reaction of the dialkyl and diaryl nitrosopyrroles with an excess of alkyl nitrite in the absence of a base can result in the formation of the nitropyrroles, whereas the reaction with nitrous acid converts the nitrosopyrroles into diazopyrroles (B-77MI30502). 

Diazotization in organic solvents allows solid diazonium salts to be isolated. Diazotization can be carried out using an ester of nitrous acid, such as pentyl nitrite, in a solvent such as acetic acid or methanol. A procedure has also been described for isolating diazonium tetrafluoroborates, in excellent yield, by carrying out the diazotization with boron trifluoride etherate and f-butyl nitrite in ether or dichlorometh-ane at low temperature. Another method for the preparation of a variety of diazonium salts in a nonaqueous medium makes use of the chemistry of bis(trimethylsilyl)amines (8). These compounds react in dichloromethane with nitrosyl chloride and other nitrosating agents which are generated in situ. Thus, benzenediazonium chloride was isolated (96%) from bis(trimethylsilyl)aniline. 

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