Oximino ketones, synthesis

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

Table 3 Synthesis of 2-aminopyrazine 1 -oxides by condensation of a-amino nitriies with 2-oximino ketones...

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 closely related reaction involves the conversion of a-oximino ketones to nitriles by pyrolysis or by the action of thionyl chloride (75%). This reaction constitutes a step in a series for the synthesis of aliphatic acids from valeric to lauric acids. 

Whereas a-amino ketones readily form imidazoles with formamide, they are often not easy to prepare. Accordingly, they can be replaced by precursors, a-oximino ketones, which can be reduced either by dithionite or using catalytic mehods in formamide at 70-100 °C. Ring closure can then be achieved by raising the temperature (Scheme 80). When a-ketol esters are used it appears that the imidazole formation may in this instance proceed by way of the oxazole. A further special case is the formation of 4,5-disubstituted imidazoles from 1-chloro-l,2-epoxides and formamide. One recent example of an application of Bredereck s method is the synthesis of the imidazolepropanol (144) from 3-bromo-2-methoxytetra-hydropyran (Scheme 81) (80AHC(27)241). 

A solution of 1.8 moles of the ketone in 800 ml. of ether is treated with the methyl nitrite generated from 2.58 moles of methanol, 2.28 moles of 95% sodium nitrite in 100 ml. of water, and 2.86 moles of coned, snifuric acid diluted with 145 ml. of water. The oximino ketone (2) is converted into the O-methyl ether (3) with dimethyl sulfate and alkali, and hypochlorite cleavage in aqueous dioxane affords the acid (4). Hydrogenation completes the synthesis of Di.-phenylalanine (5) in overall yield of 50% from (1). 

A classical synthesis of alkyl- and arylpyrazines involves dimerization of a-amino carbonyl compounds, which may be produced by many methods such as reduction of a-oximino ketones, aminolysis of a-halogeno ketones (Section 6.0T11.2), oxidation of a-amino alcohols and reduction of a-amino acids . The condensation of 1,2-diamines with a-dicarbonyl compounds is available for the synthesis of particularly quinoxaline derivatives (Section 6.03.11.1). The synthetic methods which rely on self-condensation, however, provide only symmetrically substituted pyra-... 

A new primary synthesis of 2-amino-3-arylpyrazines is accomplished by reaction of aroyl cyanides with 1,2-diaminoethane (Scheme 33). An important synthesis is that of 2-amino-3-cyano-5-sub-stituted pyrazines, which are conveniently synthesized by condensation of aminomalononitrile with a-oximino ketones and then deoxygenation of the resulting pyrazine jV-oxides (Scheme 37). 

One of the major problems encountered in this synthesis is the difficulty of obtaining the starting materials (either the a-aminocarbonyl compounds or their acylated derivatives). The former may be prepared by Neber rearrangement of ketoxime tosylates with a base such as ethoxide or pyridine.46 a-Acylamino carbonyl compounds can be prepared directly by the reductive acetylation of oximino ketones.28 38 Balaban and his collaborators47-60 have developed an excellent method for the synthesis of a-acylamino ketones (5). They are obtained in yields of 50-90% by the reaction of azlactones (2-aryl-5-oxazolone, 4) with aromatic hydrocarbons in the presence of aluminum chloride under Friedel-Crafts conditions the reaction may proceed either intermolecularly or intramolecularly. 

The intriguing structure of these steroids coupled with their potent biological activity and limited availability makes them an attractive challenge for the synthetic organic chemist. One of the key features of any attempted synthesis is the central heterocyclic ring. The classical method of pyrazine synthesis involves the dimerization of a-amino ketones. A steroidal example relevant to the cephalostatin problem was reported15 as early as 1968 (Scheme 4) androstanolone (1) was converted to a-oximino ketone 2, which was hydrogenated to afford the hydrochloride salt of a-amino ketone 3. The salt was neutralized to the free base, and condensed in situ to yield symmetrical dimer 4 in modest overall yields. 

The Knorr synthesis also proceeds via y0-enaminone intermediates 16 [40]. Frequently, the a-amino ketones are not employed as such but generated in situ by reduction of a-oximino ketones. The latter are obtained by nitrosation of ketones with alkyl nitrites in the presence of sodium methoxide ... 

The Gutknecht pyrazine synthesis has overcome the difficulty of forming the multiple regioisomers that plagued the Staedel and Rugheimer synthesis. The synthesis begins with the reduction of oximino-ketones to... 

The mechanism of Gutknecht pyrazine synthesis has been studied and is well understood. Reduction of the a-oximino ketone affords an a-amino ketone. If the reduction is carried out under acidic conditions, the a-amino ketone may be isolated as an acid salt. These acid addition salts are entirely stable. In these salts the ketone carbonyl may be hydrated, and this is particularly true for a-amino aldehydes. However, as soon as the free base of the amine is generated, either from the salt or during reduction of the oxime if this is carried out under neutral or basic conditions, rapid bimolecular imine formation occurs, which is then followed by rapid intramolecular formation of a second imine to afford a dihydropyrazine. Oxidation to the pyrazine may occur spontaneously upon exposure to air, particularly in the presence of transition metals, and it is this facile aerobic oxidation that doubtless accounts for the isolation of pyrazines by early workers in the field. 

It should be noted that there are several other means by which the key a-aminocarbonyl intermediates of the Gutknecht synthesis may be prepared besides by the reduction of a-oximino ketones. The oxidation of a-aminoalcohols, reduction of a-amino acids and their derivatives, hydrolysis of a-acetamido ketones formed from a-amino acids and acetic anhydride by the Dakin-West reaction, and the reduction of a-azido, a-diazo, and a-nitro ketones all lead to dihydropyrazines by way of a-amino ketones. The Gastaldi synthesis provides an alternate use of a-oximino ketones, to afford dicyano pyrazines. ... 

In general, the Gutknecht pyrazine synthesis allows the preparation of a wide variety of pyrazines containing symmetrically placed substituents. Yields are generally above 75%, making the reaction a useful route for preparative work. Oximino ketones derived from aralkyl ketones and p-keto esters have perhaps been used most frequently due the ease with which the ketones may be prepared and nitrosated. 

The Knorr pyrrole synthesis involves the reaction between an a-amino ketone 1 and a second carbonyl compound 2, having a reactive a-methylene group, to give a pyrrole 3. The amine 1 is often generated in situ by reduction of an oximino group. 

A way of avoiding the difficulty of handling a-aminocarbonyl-compounds is to prepare them in the presence of the second component, with which they are to react. Zinc-acetic acid or sodium dithionite can be used to reduce oximino-groups to amino, while leaving ketone and ester groups untouched, hi the classical synthesis, which gives this route its name, the a-aminocarbonyl component is simply an amino derivative of the other carbonyl component, and it is even possible to generate the oximino precursor of the amine in situP ... 

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