Dicarbonyl compounds, aldol reactions

A route to pyridines which involves an isolated 1,5-dicarbonyl compound, has been reported. Aldol reaction of enone 57 with methylketone 58 generated 1,5-diketone 59. When this was submitted to the reaction conditions for a Krohnke reaction, thiopyridine 60 was isolated. 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

Efforts were made by Garcia Gonzalez and his coworkers to elucidate the mechanism of this reaction. In one of the working hypotheses, it was considered that the aldehydo form of the sugar and the 1,3-dicarbonyl compound undergo an aldol reaction to yield a 2-C-(alditol-l-yl)-l,3-dicar-bonyl compound, which is then dehydrated to form the furan. This hypothesis was supported by the isolation of the aldol-addition product of... 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

Finally, aldol reactions can, with suitable dicarbonyl compounds, e.g. (99), be intramolecular, i.e. cyclisations ... 

Schreiber and his coworkers have published extensively over the past decade on the use of this photocycloaddition for the synthesis of complex molecules730 81. Schreiber was the first to recognize that the bicyclic adducts formed in these reactions could be unmasked under acidic conditions to afford threo aldol products of 1,4-dicarbonyl compounds (175 to 176) (Scheme 40). The c -bicyclic system also offers excellent stereocontrol in the addition of various electrophilic reagents (E—X) to the enol ether of these photoadducts on its convex face (175 to 177). This strategy has been exploited in the synthesis of a variety of architecturally novel natural products. 

The reaction itself is rather attractive and useful as a synthetic tool, because of its practical simplicity. Indeed, 1,5-dicarbonyl compounds can be readily prepared from olefin and 1,3-dicarbonyl compound in a one-pot reaction. Subsequent aldolization of the resulting 1,5-dicarbonyl compounds would furnish cyclohexenones. The reaction mechanism and stereochemistry of the de Mayo reaction has been comprehensively reviewed7), and the basic strategy of which has also been developed and extended. The following examples would demonstrate some applications and variations of the de Mayo reaction. 

Aldoses generally undergo benzilic acid-type rearrangements to produce saccharinic acids, as well as reverse aldol (retro-aldol) reactions with j3-elimination, to afford a-dicarbonyl compounds. The products of these reactions are in considerable evidence at elevated temperatures. The conversions of ketoses and alduronic acids, however, are also of definite interest and will be emphasized as well. Furthermore, aldoses undergo anomerization and aldose-ketose isomerization (the Lobry de Bruyn-Alberda van Ekenstein transformation ) in aqueous base. However, both of these isomerizations are more appropriately studied at room temperature, and will be considered only in the context of other mechanisms. 

The cationic iridium complex [Ir(cod)(PPh3)2]OTf, when activated by H2, catalyzes the aldol reaction of aldehydes 141 or acetal with silyl enol ethers 142 to afford 143 (Equation 10.37) [63]. The same Ir complex catalyzes the coupling of a, 5-enones with silyl enol ethers to give 1,5-dicarbonyl compounds [64]. Furthermore, the alkylation of propargylic esters 144 with silyl enol ethers 145 catalyzed by [Ir(cod)[P(OPh)3]2]OTf gives alkylated products 146 in high yields (Equation 10.38) [65]. An iridium-catalyzed enantioselective reductive aldol reaction has also been reported [66]. 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

The reactions discussed in this chapter that depend on the formation of enolate anions (i.e., halogenation, aldol addition, and alkylation) often proceed smoothly and under milder conditions with 1,3-diketones than with monoketones. This is because the 1,3-diketones are stronger acids and therefore can form the enolate anions with weaker bases. The principal synthetic methods for preparing 1,3-dicarbonyl compounds will be discussed in Chapter 18. 

In the Weiss reaction (Scheme 4), an 7-dicarbonyl compound (38) condenses with two molecules of dimethyl 3-oxoglutarate (39 E = CC Me) to give a c w-bicyclo [3.3.0] oct-ane-3,7-dione tetraester (40) the one-pot reaction produces considerable complexity, with the sequential formation of four C—C bonds. Simple acid treatment removes the carbomethoxy groups, if deshed. While die reaction involves aldol and Michael sequences, die intermediacy of a cyclopentenone [4-hydroxycyclopent-2-enone (41)] has up to now been unproven. A series of such 1 1 adducts has now been reported for a variety of diketones, together with evidence diat diey are indeed intermediates en route to the bicyclo system.62 Electronic and steric effects on the reaction are also discussed in detail. 

In the case of (11), retrosynthetic functional group interconversion into the aldol followed by disconnection of the a, /3-bond gives the dipolar synthon (15), of which the reagent equivalent is the 1,4-dicarbonyl compound, hexane-2,5-dione (i.e. a refro-aldol condensation). The action of base on this diketone effects the forward aldol reaction followed by spontaneous dehydration (see Expt 7.4 for formulation). 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

The intramolecular aldol reactions reported so far can be divided into two different types. The first is a enantioselective aldol reaction starting from a dicarbonyl compounds of type 81. In these reactions, products with two stereogenic centers, 82, are formed. The reaction is shown in Scheme 6.39, Eq. (1). These products can be converted into derivatives, particularly lactones. 

Attempts to react enol(ate)s of esters with aliphatic aldehydes are doomed as the aldehyde will simply condense with itself. If the ester is replaced by a malonate 60, there is so much enol(ate) from the (5-dicarbonyl compound that the reaction is good. This style of aldol reaction is often called a Knoevenagel reaction10 and needs only a buffered mixture of amine and carboxylic acid. The enol reacts with the aldehyde 61 in the usual way and enolisation of the product 62 usually means that dehydration occurs under the conditions of the reaction. 

The sequence of cyclohexene cleavage and aldol reaction on the dicarbonyl product gives ring-contracted cyclopentenes. This proved particularly valuable when Iwata6 wanted to make subergorgic acid 41 that has three five-membered rings awkwardly joined around a quaternary carbon atom. So crowded are these compounds that they are difficult to draw clearly. Ozono-lysis of the synthetic cyclohexene 38 gave the unstable dialdehyde 39 that cyclised by an aldol condensation to 40 and hence could be oxidised to 41. 

Heterocyclic aroma compounds found in meat primarily arise from interactions between mono- and dicarbonyl compounds, H2S and ammonia. The carbonyl compounds are derived from the Maillard reaction, including Strecker degradation of amino acids, oxidation of lipids and aldolization reactions. H2S is produced by thermal degradation of sulfur amino acids and ammonia by amino acid pyrolysis. 

When a normal carbonyl compound is treated with catalytic acid or base, we have a small proportion of reactive enol or enolate in the presence of large amounts of unenolized electrophile. Aldol reaction (self-condensation) occurs. With 1,3-dicarbonyl compounds we have a small proportion of not particularly reactive unenolized compound in the presence of large amounts of stable (and hence unreactive) enol. No aldol occurs. 

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