Intramolecular aldol condensation reactions product

We recall that intramolecular aldol condensation reactions can occur to give five- or six-membered ring compounds (Section 22.9). An intramolecular Claisen condensation, known as the Dieckmann condensation, can also occur to give five- or six-membered ring compounds. The Dieckmann condensation is more favorable than the bimolecular Claisen condensation because it converts a single molecule of reactant into two molecules of product. 

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]. 

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. 

J0rgensen has also reported a sequential Michael/Michael/aldol condensation for the three component coupling of malonitrile 111 and a,P-unsaturated aldehydes that involves two iminium ion catalysed Michael additions followed by an intramolecular aldol condensation (Scheme 43) [170]. Using diarylprolinol ether 55 (10 mol%) in a concentrated toluene solution of malonitrile 111 and 3 equivalents of a,P-unsaturated aldehyde the reaction products can be isolated in just 1 8 h (57-89% yield 97-99% ee). The atom efficiency of this three component reaction is remarkable and the ability to prepare these complex products under... 

The proposed mechanism involves the formation of ruthenium vinylidene 97 from an active ruthenium complex and alkyne, which upon nucleophilic attack of acetic acid at the ruthenium vinylidene carbon affords the vinylruthenium species 98. A subsequent intramolecular aldol condensation gives acylruthenium hydride 99, which is expected to give the observed cyclopentene products through a sequential decarbonylation and reductive elimination reactions. 

Rate and equilibrium constants have been measured for representative intramolecular aldol condensations of dicarbonyls.60a For the four substrates studied (32 n = 2, R = Me n = 3, R = H/Me/Ph), results have been obtained for both the aldol addition to give ketol (33), and the elimination to the enone (34). A rate-equilibrium mismatch for the overall process is examined in the context of Baldwin s rales. The data are also compared with Richard and co-workers study of 2-(2-oxopropyl)benzaldehyde (35), for which the enone condensation product tautomerizes to the dienol60b (i.e. /(-naphthol). In all cases, Marcus theory can be applied to these intramolecular aldol reactions, and it predicts essentially the same intrinsic barrier as for their intermolecular counterparts. 

The catalyzed reaction of 1 with a,P-enals takes an unexpected course. The adduct with methacrolein, for example, obtained after silyl ether cleavage does not contain the expected aldehyde group, but has the bicyclic structure 5. Apparently the initial product a undergoes an intramolecular aldol condensation to give b. which undergoes silyl transfertoc, which is hydrolyzed by acid to the 7-hydroxy-bicyclo[2.2.1 Jheptanone 5. 

A broad variety of special aldehydes and ketones are easily accessible by Heck-type reactions with allylic alcohols and their homologs [3]. The potential for the synthesis of carbocydic structures is illustrated by the macrocyde 11 [4] which obviously is the product of a fourfold Heck reaction (Scheme 3). A domino process consisting of a double Heck reaction followed by an intramolecular Aldol condensation leads to the annulated ring system 15 [5]. 

Often, the Michael addition product is not isolated. Instead, the intramolecular aldol condensation occurs immediately, and the new six-membered ring is formed, as shown in the following equation. (However, when you are attempting to write the product of such a reaction, it is best to first write the product of Michael addition and then write the final product that results from the aldol condensation.)... 

Intramolecular aldol condensations often present the possibility of the formation of several products. The reaction of 6-oxoheptanal gives the product shown in the following equation ... 

Cp 2La CH(SiMe3)2 reacts with 3-pentanone to form the solvated enolate, Cp 2La —O—C(Et)=CHMe Et2CO (equation 9a), while with acetone it forms a chelate (equation 9b) after intramolecular aldol condensation. The reaction of the precursor bistrimethylsi-lyhnethyl organometallic with hydroxyketone, preformed from the pentanone, yields the enolate ketone solvate. This difference between acetone and 3-pentanone presumably reflects the difference in strain in the condensation product because the ethyl groups in 3-pentanone are rather much bigger than the methyl groups in acetone. 

As a side product, a new six-membered ring system was obtained. Three aldol condensation reactions of phenylmethylketone occurred. The last one led to an intramolecular ring closure. 

Intramolecular aldol condensation of 2,7-octanedione might give either of two cyclic products, A or B. Use SpartanView to compare the energies of transition state A and transition state B for the ring-forming step, and tell which product would be obtained if the reaction were kinetically controlled. 

The similar carbonylation proceeds when the reaction of aromatic aldimine is conducted under carbonylation reaction conditions (Eq. 28) [42]. The acylat-ed products converts to the corresponding indenone derivatives via intramolecular aldol condensation. For this reaction, ethylene, ferf-butyl ethylene, and trimethylvinylsilane react with aromatic aldimine smoothly to provide the inde-nones in high yields. 

Intramolecular aldol condensations. Swiss chemists have reported two examples of preparation of cyclic aldols by reaction of f-oxo-a,j3-enones by conjugate addition of dimethylcopperlithium followed by a directed intramolecular aldol condensation. Both aldols are products of kinetic control they are not... 

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