Diketones, intramolecular aldol condensation

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Intramolecular Claisen condensations can be carried out with diesters, just as intramolecular aldol condensations can be carried out with diketones (Section 23.6). Called the Dieckmann cyclization, the reaction works best on 1.6-diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic /3-keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic /3-keto ester. 

The first step of the Robinson annulation is simply a Michael reaction. An enamine or an enolate ion from a jS-keto ester or /3-diketone effects a conjugate addition to an a-,/3-unsaturated ketone, yielding a 1,5-diketone. But as we saw in Section 23.6,1,5-diketones undergo intramolecular aldol condensation to yield cyclohexenones when treated with base. Thus, the final product contains a six-membered ring, and an annulation has been accomplished. An example occurs during the commercial synthesis of the steroid hormone estrone (figure 23.9). 

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to a /3-hydroxy aldehyde or ketone and then to an cr,/6-unsaturated product. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl aceto-acetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five-and six-inembered rings. 

Intramolecular aldol condensation.1 This base can be effective for intramolecular aldol condensation of extremely hindered diketones that resist cyclization with the usual bases. 

The simplest approach which can be envisaged to 4/f-pyrans involves the ring closure of 1,5-diketones. However, such molecules are frequently able to undergo a facile intramolecular aldol condensation leading to cyclohexenones, which competes successfully with cyclization to the pyran. 

Di- and polysubstituted pyrrolizines are uncommon. The only pyrrolizine isolated from the intramolecular aldol condensation of 2-acetyl-l-(butan-3-on-l-yl)pyrrole was the 6,7-disubstituted compound 223.122 A small amount of the 5,6-disubstituted pyrrolizine (145d) was obtained when the 2-formylpyr-ryl anion was condensed with l,2-di(phenylsulfonyl)ethene.90 By contrast with the production of the single isomer (223), the homologous diketone 224... 

Hydrogenation of 1,4- and 1,5-diketones over platinum metals may be accompanied by cyclization to give tetrahydrofurans and terahydropyrans, respectively.133,134 The hydrogenation of 2,6-heptanedione over Pt-C at 200°C in cyclohexane gave 40% of 2,6-dimethyltetrahydropyran, together with 43% of 3-methylcyclohexanone and 15% of 3-methylcyclohexanol, which resulted by an intramolecular aldol condensation and subsequent hydrogenation.134... 

The intermediate 1,5-diketone undergoes an intramolecular aldol condensation to yield a cyclohexenone. 

Oxonine diketone 132 (Scheme 23) is highly sensitive to acidic conditions and prone to intramolecular aldol condensation. The sole product of the process, 4-oxocyclopenta[c]pyran-l-carboxylate 133, was isolated in 94% yield, and the regiochemistry of the process was assigned by X-ray crystal stmcture of the related amide aldol adduct <20020L3059>. 

Subsequently the trisanellation reagent, 7-acetoxy-l,ll-dodecadien-3-one 0M>) was prepared from the bisanellation reagent (67), and the synthesis of D-homo-19-norandrosta-4-en-3-one (82) was carried out from (79) as shown below. For the A-ring formation, the unmasking of the termi double bond and hydrogenation afforded the 1,5-diketone (81), which was subjected to intramolecular aldol condensation to give D-homo-4-androstene-3,17a-dione (82 Scheme 23). 

Bouillon, J.-P., Portella, C., Bouquant, J., Humbel, S. Theoretical Study of Intramolecular Aldol Condensation of 1,6-Diketones Trimethylsilyl Substituent Effect. J. Org. Chem. 2000, 65, 5823-5830. 

Intramolecular Aldol Condensation of 1,5-Diketones 6-exo-trig favored process... 

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