J8-dicarbonyl compounds

Condensation of 1,2-diaminopropane and 2,3-dioxobutane similarly gives 5,6-dihydro-2,3,5-trimethylpyrazine which is oxidized to the corresponding pyrazine in 58% yield by treatment with potassium hydroxide pellets.111 Hydroxypyrazines are very conveniently prepared from a,j8-dicarbonyl compounds and a-amino acid amides [Eq. (1)],30,112 and pyrazinecarboxylic acids have been prepared by condensation of an a,)5-diketone with an a,/ -diaminocarboxylic acid, followed by oxidation (Scheme 2). Thus, condensation of benzil and... 

Diaminopyrazines undergo the expected condensation reactions with a,j8-dicarbonyl compounds. For example, condensation of 2,3-diamino-5,6-dimethylpyrazine with a,/9-diketones gives pyrazino-[2,3-h]pyrazines (124).38 2,3-Diaminopyrazines are also starting materials for the preparation of imidazo[4,5-6]pyrazines (123).117... 

These compounds are synthesized (see Section III) by the condensation of a,j8-dicarbonyl compounds with 1,2-diamines. Thus,... 

The parent 1,2-dithiolylium ion (4) is readily prepared by treatment of l,2-dithiole-3-thione (3b R = R = H) with hydrogen peroxide in acetic acid (65JCS32). The method may be applied to the alkyl and aryl derivatives with equal success. For cations with 3- and 5-substitution the acid catalyzed reactions of j8-dicarbonyl compounds with hydrogen disulfide or equivalent are best (80AHC(27)l5i), whereas the benzo-1,2-dithiolylium ion (172) and related compounds are best prepared by ring contraction of benzo-l,3-dithiins (171) (63LA(661)84>. 

Apart from a few exceptions [13], the quadrant model can be employed to predict the asymmetric induction of BINAP complexes. For example, the model can be referred to when considering the reduction of j8-dicarbonyl compounds (Scheme 5). In 24, repulsion between the equatorial phenyl moiety and R occurs when the substrate adapts the orientation where the keto function is com-plexed coparallel to the Ru-H bond, which is... 

Strategy Hydrogens on carbon next to a carbonyl group are acidic. In general, a j8-dicarbonyl compound is most acidic, a ketone or aldehyde is next most acidic, and a carboxylic acid derivative is least acidic. Remember that alcohols, phenols, and carboxylic acids are also acidic because of their -OH hydrogens. 

When a-hydroxyimino-j8-dicarbonyl compounds are refluxed with allylamine, the products are 2-vinylimidazoles (Equation (69)) < 855300). 

In contrast to the 3-substituted products above, 4-chloro-, 4-bromo- and 4-iodo-isoxazoles are readily prepared by direct halogenation of the corresponding isoxazoles, from 4-isoxazolediazonium salts by the Sandmeyer reaction, or by reaction of hydroxylamine with a -halo-j8-dicarbonyl compounds (62HC(l7)l, p. 66, 63AHC(2)365). 3,5-Bis(dimethyl-amino)-4-fluoroisoxazole has been synthesized by reaction of (Me2NCO)2CHF with hydroxylamine (78BSB391). 

Tricarbonyl monohydrazones (e.g. (252)), prepared by classical Japp-Klingermann coupling of aryl diazonium salts with j8-dicarbonyl compounds, undergo condensation with sulfamide to yield... 

A new synthesis of corydolactam (19) ( alkaloid P ) has been reported (Scheme 2). Advantage was taken of a known reaction of 1-toluene-p-sulfonylaziridine (16) with j8-dicarbonyl compounds to prepare the pyrrolidone (17), which upon ketalization and detosylation yielded (18), a compound previously transformed in two steps into corydolactam (19). 

The preparation of yS-enamino ketone and esters on solid montraorillonite KIO day coupled with MW irradiation applies to cydic, acyclic and a-chloro-substituted j8-dicarbonyl compounds with amines or their corresponding ammonium acetates (Scheme 8.26) [80]. 

Indole-3-carboxylate esters and 3-acetylindoles can be prepared by palladium-catalyzed cycli-zation of enamines (14). These can be prepared from the corresponding anilines by condensation with j8-dicarbonyl compounds or by palladium-catalyzed substitution reactions with ethyl acrylate or methyl vinyl ketone <86BCJ927, 90S215>. Overall yields for the two-step process are 60-80% (Scheme 33). 

The Hantzch pyrrole synthesis is a variation of this reaction which is conducted as a three component synthesis from a j8-dicarbonyl compound, an a-haloketone or aldehyde and anunonia or an amine (Equation (38)). Yields for this procedure are typically 20-50% <7oaci689>. The regiochemistry is that resulting from N—C bond formation at the carbonyl carbon of the a-haloaldehyde. 

The chiral phosphoric acid (123)-catalyzed highly enantioselective a-hydroxylation of j8-dicarbonyl compounds (138) and (139) to give (141) or (142) through a tandem aminoxylation/N-O bond heterolysis sequence using nitroso compounds, such as (140), as the oxygen source, has been described by Zhong et al. (Scheme 37). ... 

In contrast, j8-dicarbonyl compounds, such as malonic ester and acetoacetic ester, are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

First we compare the acidity advantages of j8-dicarbonyl compounds, and then we consider how these compounds are used in synthesis. 

In compounds whose molecules have two carbonyl groups separated by one carbon atom (called j8-dicarbonyl compounds), the amount of enol present at equilibrium is far higher. For example, pentane-2,4-dione exists in the enol form to an extent of 76% ... 

Two specific j8-dicarbonyl compounds have had broad use in organic synthesis. These are acetoacetic ester (ethyl acetoacetate, ethyl 3-oxobutanoate), which can be used to make substituted acetone derivatives, and diethyl malonate (diethyl 1,3-propanedicarboxylic acid), which can be used to make substituted acetic acid derivatives. We shall consider syntheses involving ethyl acetoacetate and diethyl malonate in the upcoming sections of this chapter. 

Acetoacetic ester, because it is a j8-dicarbonyl compound, can easily be converted to an enolate using sodium ethoxide. We can then alkylate the resulting enolate (called sodio-acetoacetic ester) with an alkyl halide. This process is called an acetoacetic ester synthesis. 

Oxidation of j8-dicarbonyl compounds by f-butyl hydroperoxide in the presence of vanadyl acetylacetonate [VO(acac)2] in benzene results in decomposition of the carbon skeleton, via intermediate trioxo derivatives." ... 

The synthesis of ketones from j9-keto-sulphoxides shows the comparability of these compounds with j8-dicarbonyl compounds. " Other synthetic uses include the formation of a-chloro-oximes RC(Cl)=NOH on nitrosation... 

The greater stability of the enol form of j8-dicarbonyl compounds can be attributed to resonance stabilization of the conjugated double bonds and (in a cyclic form) through hydrogen bonding. 

A much weaker base than LDA, such as an alkoxide, can be used to form an enolate from a j8-dicarbonyl compound. 

The enamine-Michael reaction has two advantages over the enolate-ion-Michael reaction that makes it particularly useful in biological pathways. First, an enamine is neutral, easily prepared, and easily handled, while an enolate ion is charged, sometimes difficult to prepare, and must be handled with care. Second, an enamine from a monoketone can be used in the Michael addition, whereas enolate ions only from j8-dicarbonyl compounds can be used. 

Having seen how to prepare j8-dicarbonyl compounds, let us explore their synthetic utility. This section will show that the corresponding anions are readily alkylated and that 3-ketoesters are hydrolyzed to the corresponding acids, which can be decarboxylated to give ketones or new carboxylic acids. These transformations open up versatile synthetic routes to other functionalized molecules. 

Working with the Concepts Syntheses Using j8-Dicarbonyl Compounds... 

Pyridines can be made by condensation reactions of acyclic starting materials such as carbonyl compounds with ammonia. The most general of these methods is the Hantzsch pyridine synthesis. In this reaction, two molecules of a j8-dicarbonyl compound, an aldehyde, and ammonia combine in several steps (Worked Example 25-28) to give a substituted dihydropyridine, which is readily oxidized by nitric acid to the aromatic system. When the j8-dicarbonyl compound is a 3-ketoester, the resulting product is a 3,5-... 

An improved method (Scheme 40) for the synthesis of stabilized primary enamines (69) from j8-dicarbonyl compounds utilizes the easily prepared N-trimethylsilyliminotriphenylphosphorane (68). The observation that no reac-... 

Both aliphatic and aromatic isocyanates can be blocked by a variety of blocking agents. These include alcohols, phenols, oximes, lactams, j8-dicarbonyl compounds, bisulfite addition compounds, hydroxylamines and esters of p-hydroxybenzoic acid and salicylic acid. Perhaps the most widely used blocking agents at present are phenol, branched alcohols, 2-butanone oxime (methyl ethyl ketoxime) and 8-caprolactam. The use of blocked isocyanates in PU coatings has been comprehensively reviewed. ... 

---