1,3-Dicarbonyl type compounds carbon acidity

Support-bound carbonyl compounds can be converted into alcohols by treatment with suitable carbon nucleophiles. Aldehydes react readily with ketones or other C,H-acidic compounds under acid- or base-catalysis to yield the products of aldol addition (Table 7.2). Some types of C,H-acidic compound, such as 1,3-dicarbonyl compounds, can give the products of aldol condensation directly (Section 5.2.2.2). 

Numerous examples of the preparation of tetramic acids from N-acylated amino acid esters by a Dieckmann-type cyclocondensation have been reported (Entries 7-9, Table 15.4). Deprotonated 1,3-dicarbonyl compounds and unactivated amide enolates can be used as carbon nucleophiles. In most of these examples, the ester that acts as electrophile also links the substrate to the support, so that cyclization and cleavage from the support occur simultaneously. The preparation of five-membered cyclic imi-des is discussed in Section 13.8. 

The presence of two, or even three, electron-withdrawing groups on a single carbon atom makes the remaining proton(s) appreciably acidic (pKa 10-15), which means that even mild bases can lead to Complete enolate formation. With bases of the strength of alkoxides or weaker, only the multiply stabilized anions form protons adjacent to just one carbonyl group generally have a p Ca > 20. The most important enolates of this type are those of 1,3-dicarbonyl (or 3-dicarbonyl) compounds. 

The importance of fluorinated organic componnds both in medicinal chemistry and biochemistry has resulted in much recent attention towards efficient carbon fluorine bond formation [30]. The reactions developed include a very successful electrophilic asymmetric mono-fluormation of 1,3-dicarbonyl compounds [31]. A nucleophilic variant was also investigated. In this context, the groups of Togni and Mezzetti have established that ruthenium Lewis acids could efficiently catalyze fluorination reactions [32]. In the presence of [Ru(l,2-bis(diphenylphosphino)ethane)2Cl][PF6] (8) (10 mol%), fert-butyl iodide reacted at room temperature with TIF (1.1 equiv.) to yield fert-butyl fluoride (84% yield). This reaction was extended successfully to a range of organic halides (Entries 1-3, Scheme 10.19). The use of the chiral complex [Ru((lS,2S)-N,N bis[2-diphenylphos-phino)benzylidene]diaminocydohexane))Cl][PF6] (9) showed modest chiral induction at the outset of the reaction (Entry 4, Scheme 10.17). The near-racemic mixture obtained at completion points to an SNl-type process in this nucleophilic halide... 

Electrochemical oxidation of thiophene derivatives in methanol at a Pt anode leads to different types of reactions depending upon the electrolytes used. With sodium meth-oxide, 2,5-dimethyl- and tetramethylthiophene [207] afforded 2,5-dimethoxy adducts as a mixture of cisitrcms isomers together with side-chain oxidation products. However, in the presence of sodium acetate, the latter become the main products. In methanol/sulfuric acid solutions, at a carbon anode, thiophene and derivatives [208] oxidations resulted in a ringopening reaction with loss of the sulfur atom, yielding y-dicarbonyl compounds and their... 

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

Aldol reactions of this type, involving 2-acetamido-2-deoxyaldohexoses, have been studied in connection with the chemical synthesis of A -acetyl-neuraminic acid (50) and related substances, and, for this reason, the choice of the dicarbonyl compound has thus far been limited to oxalacetic acid and its esters. Oxalacetic acid condenses readily with 2-acetamido-2-deoxyaldohexoses in aqueous solution at pH 11. Under these conditions, acetamido sugars partially epimerize, and the aldol reaction takes place for both of the 2-acetamido-2-deoxyaldohexoses present. The complexity of the reaction is further increased by the formation of asymmetric centers at carbon atoms 3 and 4 of the condensation products, namely, diacids (45) and (48), and this can result in the formation of four diastereo-isomers from each sugar. The reaction using 2-acetamido-2-deoxy-o-rnannose (47) has been the one most extensively studied. In this... 

C-2 modification of the 1,3-dicarbonyl compound is possible by deprotonation in the 2-position followed by electrophilic capture (path A). Depending on the type of electrophile used, oxygen modification is also possible (path B). Nucleophilic attack on one of the Meldrum s adds carbonyl groups leads to a tetrahedral intermediate, which decomposes easily to generate carbon dioxide, acetone, and an enolate product, which is protonated either by addic leadion media or in a separate work-up step. This nucleophilic displacement reaction equals the use of Meldrum s acid as a —CH CCO) equivalent. Indeed, this is a very common application of Meldrum s acid in multicomponent syntheses (vide infra). 

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