Methylene groups, nitrosation

A zinc-free alternative to the Knorr pyrrole synthesis employs catalytic hydrogenation, as for 17 + 18 to 19. Oximes such as 17 are readily prepared by nitrosation (NaNOa, HO Ac) of the active methylene group. 

According to patent descriptions (Scheme 76), activated methylene groups were reacted with nitrosating agents and with dimethylformamide to yield oximes, such as 332, and oc-aminomethylene ketone 334, respectively (73USP3780043, 99W032453). 

Gucky et al. prepared oximes 91 by nitrosation of the activated methylene group of 87 using nitrosylsulfuric acid and sodium nitrite in concentrated sulfuric acid (Scheme 68) <2002HC0613>. Oximes 91 were treated with hot POCI3 to induce a five-membered cyclization to provide the fused isoxazole ring in 92. The overall yields for transforming 87 to 92 are shown in Table 5. 

The three preparative methods which are illustrated in this section are (a) the oxidation, or (b) the nitrosation, of the a-methylene group in a symmetrical ketone or an aryl alkyl ketone (Expts 5.99 and 5.100), and (c) the oxidation of alkynes under PTC conditions (Expt 5.101). 

Alkyl methyl ketones undergo nitrosation at the reactive methylene group when treated with nitrous acid or an alkyl nitrite [Method (fi)]. The presence of hydrogen on the a-carbon permits tautomeric rearrangement to the oxime of a 1,2-dicarbonyl compound. Acidic hydrolysis of the oxime, which is best carried out in the presence of a hydroxylamine acceptor such as laevulinic acid,143 affords a further useful route to the 1,2-dicarbonyl system. 

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). 

The a-aminoketones are often prepared by nitrosation of an active methylene group followed by reduction of the oxime to the amine (e.g. 2.25 to 2.26 to 2.27). 

In order to synthesize 17-a-hydroxyaldosterone 2a,12 a side chain protection was needed. Otherwise the 18-carbon radical tended to furnish a methylene group and open the 13-17 bond in ring D. A convenient protection for the corticoid side chain is the A/.v-ketal derived from formaldehyde. Thus Msmethyl-enedioxy-1-dehydrohydrocortisone 21 was converted to its nitrite and photolyzed in the usual way. The only product (60 % isolated yield) was the desired isomer 22. When this was treated with nitrous acid, an unusual sequence of reactions took place. The normal nitrosation intermediate underwent ring closure to 24 followed by oxonium ion formation 25 as indicated. The oxonium ion 25 then opened one of the adjacent methylenedioxy groups (25 -> 26) which on hydration with water afforded the isolated product 27. Acetylation of 27 with acetic anhydride and acid catalysis gave the triacetate 28 in 80 % overall yield from the oxime 22. Mild alkaline hydrolysis... 

Similarly, the a-methylene group of acetoacetic ester is oximinated by the action of sodium nitrite in glacial acetic acid (63%). Nitrosation of alkylated malonic, acetoacetic, and benzoyl acetic esters with subsequent cleavage affords an excellent synthesis for a-oximino esters, RC(=-NOH)COjC2Hj. A survey of several possible procedures for this conversion has been made." If a /3-keto acid is nitrosated, then the Carboxyl group is lost and an a-oximino ketone is formed, viz.,... 

A general reaction for the formation of the pyrrole nucleus consists in the treatment of an a-amino ketone with another ketone having a reactive a-methylene group. The a-amino ketone is conveniently prepared from the ketone by nitrosation and reduction and then, without isolation, it is allowed to condense with a second carbonyl compound, viz.,... 

Nitrosobenzene, CjHsNO, which is obtained by the oxidation of phenylhydroxylamine, and p>nitrosodimethylaniline, p-(CH3)2NCjH4NO, which is easily prepared by the nitrosation of dimethylaniline, are fairly specific oxidizing agents for the preparation of aromatic aldehydes from benzyl halides or tosylates and of a-dicarbonyl compounds from from a-halo ketones [984, 985]. Also, a methylene group flanked by two carbonyls can be oxidized to a carbonyl group by nitrosodimethylaniline [986]. Pyridine is frequently used to form quaternary pyridinium salts from reactive halides prior to their oxidation to aromatic aldehydes, a-ketoaldehydes, or a-diketones [984] (equations 22 and 23). 

IJC(B)132 86JHC1439]. Attempted nitrosation of the methylene group of 1,3-thiazol-2-ylhydrazone (115) proceeded with the simultaneous formation (80JHC1321) of the title fused-ring system to give 116. 

C-Formylation or a-oximation of the highly hindered a-methylene group in the parent ketone is not possible. Direct transfer of the diazo group from tosyl azide under phase transfer conditions has been found unproductive.19 A variety of highly hindered ketones are converted to corresponding diazo ketones with 2,4,6-triisopropylphenylsulfonyl azide under phase-transfer conditions.19 Tetrabutylammonium bromide and 18-crown-6-ether are used as catalysts in these diazo transfer reactions. This method is superior to C-nitrosation followed by diazotization with chloramine. The diazo compounds 66 (55%) and 68 (72%) are obtained using this method. 

Keto esters and amides containing unsubstituted a-methylene groups can be nitrosated to give <%-(hydroxyimino) / -keto esters and amides. For example, <%-(hydroxyimino)acetoacetic ester is formed almost quantitatively on dropping an aqueous sodium nitrite solution into a cooled mixture of acetoacetic... 

For the preparation of oximes by nitrosation of compounds containing active methylene groups see page 428. 

The hydroxyimino group attached to carbon (C=NOH) may be converted into an amino group by way of the intermediate hydroxyamino or imino group. The reduction of oximes can be conducted so as to yield (1) a synthesis of amines from carbonyl compounds, (2) introduction of amino groups into a compound containing active methylene groups (by way of the isonitroso compounds obtained by nitrosation), or (3) production of amines from the adducts of nitrogen oxides or nitrosyl chloride to olefins. 

Reactions of the methylene group Reactions at the methylene group of the molecule yield dicyanomethylene compounds in many cases. These will be discussed in Section III. A. 3 in detail. Some compounds have been reported, which result from reactions at the methylene group of 10 but are no classical dicyanomethylene compounds. So, for example, nitrosation with nitrous acid in the presence of nucleophilic catalysts yielded the corresponding oxime product (NC)2C=N0H42. 

Nitrosation is almost equally rare. 2-Picoline failed to react with butyl nitrite under either basic or acidic catalysis. The sodium derivative does react247 j and the reaction is mentioned under Section (/) below. 4-Pyridyl-acetonitrile has been nitrosated at the methylene group, but details have not been given . ... 

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 behavior of bis(heteroaryl)methanes in which the heterocycle was an electron-withdrawing group was similar to that typically exhibited by active methylene compounds. Bis(2-benzothiazolyl)methane and bis(2-(5-ethoxycarbonyl-4-methyl)thiazolyl)methane readily underwent azo-coupling with benzenediazonium chloride, nitrosation with nitrous acid and condensation with aromatic aldehydes under mildly basis conditions, such as in the Knoevenagel procedure. [94G301]... 

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