Ketones nitrosation

Biacetyl is produced by the dehydrogenation of 2,3-butanediol with a copper catalyst (290,291). Prior to the availabiUty of 2,3-butanediol, biacetyl was prepared by the nitrosation of methyl ethyl ketone and the hydrolysis of the resultant oxime. Other commercial routes include passing vinylacetylene into a solution of mercuric sulfate in sulfuric acid and decomposing the insoluble product with dilute hydrochloric acid (292), by the reaction of acetal with formaldehyde (293), by the acid-cataly2ed condensation of 1-hydroxyacetone with formaldehyde (294), and by fermentation of lactic acid bacterium (295—297). Acetoin [513-86-0] (3-hydroxy-2-butanone) is also coproduced in lactic acid fermentation. 

Methyl isothiazole-4-acetate is nitrosated by pentyl nitrite, and the oximino ester formed can be hydrolyzed to the a-keto ester (78GEP2745246). Secondary alcohols (94) can be oxidized to the ketones (72GEP2223648). 

Carbons adjacent to a Z group (as defined on p. 548) can be nitrosated with nitrous acid or alkyl nitrites. The initial product is the C-nitroso compound, but these are stable only when there is no tautomerizable hydrogen. When there is, the product is the more stable oxime. The situation is analogous to that with azo compounds and hydrazones (12-7). The mechanism is similar to that in 12-7 R—H —> R + N=0 — R—N=0. The attacking species is either NO or a carrier of it. When the substrate is a simple ketone, the mechanism goes through the enol (as in halogenation 12-4) ... 

The above procedure2 is modeled after that described for the nitrosation of arylethyl ketones.4-5 w-Chloroisonitroso-acetophenone has been prepared by the chlorination of isonitro-... 

Because of their interest in physiologically active selenophenes, Magde-sieva and co-workers147 I4S have prepared some a-amino alcohols (115). Ketones (114) were nitrosated and the oximes thus obtained were reduced with lithium aluminium hydride. 

The cyclobutanone (255) reacted with acid to furnish the keto-acid (259). Upon esterification, ketalization and reduction, (259) was converted to the alcohol (260). Mesylation of the alcohol (260) and then treatment of the mesylate with NaN3 in DMSO provided the azide (261). The azide (261) was then transformed to the urethane (262) by reduction and ethyl chloroformate reaction. The urethane (262) was deketalized by acid, nitrosated by N204—NaOAc and decomposed by NaOEt—EtOH to give the ketone (263) 89). The ketone (263) served as a starting material for the synthesis of veatchine (264)90). 

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). 

The ready accessibility of 1,2-dioximes (glyoximes) and the ease with which they are dehydrated has ensured that this is the most common route to furazans. The starting materials are usually prepared by oximation of the appropriately substituted 1,2-diketone or, more often, by a-nitrosation of an alkyl ketone followed by oximation of the resulting 1,2-dione monooxime (Scheme 16). 1,2-Dioximes can also be prepared by reduction of furoxans (Section 4.05.5.2.4) and, in cases where the furoxan is more readily available than the furazan, for example, by nitrile oxide dimerization, this furoxan-> glyoxime-> furazan sequence represents a viable synthetic strategy for symmetrically substituted derivatives. 

Assuming that the above rationale for tertiary amine nitrosation was valid, we predicted 3) that the reaction of secondary amines with nitrite at milder pH s should be catalyzed by electrophilic carbonyl compounds, since secondary amines are known to form immonium ions on admixture with appropriate aldehydes and ketones. The prediction turned out to be true. Formaldehyde was shown to promote nitrosamine formation from a... 

The anion formed from the acetyl methyl group under reaction conditions then attacks one of the carbethoxy groups to form a cylohexanone to give (74-4) as the isolated product. The free acid obtained on hydrolysis of the ester decarboxylates to give the (3-diketone (74-5). In a classic apphcation of the Knorr pyrrole synthesis, the diketone is then allowed to react with 2-aminopentan-3-one. Since the latter is unstable, it is generated in situ by reduction of the nitrosation product from diethyl ketone. There is thus obtained piquindone (74-6) [76], a compound that displays antipsychotic activity. 

In the nitrosation of ethyl isopropyl ketone (Preparation 2-4), acetyl chloride is used as a catalyst. While aqueous hydrochloric acid has also been used to catalyze this reaction, anhydrous hydrogen chloride or acetyl chloride evidently is more effective as far as the yield is concerned. To be noted here is that the greater yield is that of the true nitroso compound. However, the secondary carbon atom of the ethyl group is converted into an oxime on nitrosation. 

Treatment of aliphatic active methylene compounds with such reagents normally leads to oxime formation. An exception is the nitrosation of compounds with active tertiary carbon atoms such as ethyl isopropyl ketone which are convertible into C-nitroso compounds. 

The preparation of iV-nitroso-/5-alkylaminoisobutyl ketones is of particular interest as a method for preparing the intermediates for the diazoalkane synthesis. The preparation of these compounds is based on the addition of a primary amine to mesityl oxide to give a secondary amino ketone which is then nitrosated (see Volume I, Chapter 15, Section 2A,g). This preparation uses an... 

Evidence is that the reaction, in the presence of X" (Br, Cl , or SCN ) was first order in ketone and in H , but zero order in HN02 and X. 159 Furthermore, the rate of the nitrosation was about the same as that for enolization of the same ketones. The species NOX is formed by HONO + X + FT - HOX + H20. In the cases of F.,CCOCH2COCF3 and malon-onitrile the nitrosation went entirely through the enolate ion rather than the enol.16,1... 

Many of the methods discussed in this section can also be treated as combinations of more than two fragments. For instance, in the cyclization of a-hydrazono oximes with orthocarboxylates described in the next section, the a-hydrazono oximes (635) are treated as a five-atom fragment, but since these compounds are usually prepared from ketones by nitrosation and reaction of the oximino ketones with hydrazine, the entire reaction sequence may be described asa[2 + l+ 2+ l] combination. 

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