Dieckmann reaction ester groups

After converting A -Phth-protected amines into the corresponding 2-(pyrrolidinocarbon-yl)benzamide derivative, Dieckmann reactions, ester hydrolysis, and transesterfication can be carried out. This strategy of pyrrolidine-based deactivation of phthaloyl-protected anoines followed by reclosure of the phthaloyl group has successfully been applied in the synthesis of (3-lactam antibiotics.P l... 

We begin with the discussion of intramolecular reactions. An example of a regioselec-tive Dieckmann condensation (J.P. Schaefer, 1967) used an educt with two ester groups, of which only one could form an enolate. Regioselectivity was dictated by the structure of the educt. 

The carbon-car bon bond-fonrring potential inherent in the Claisen and Dieckmann reactions has been extensively exploited in organic synthesis. Subsequent transfonnations of the p-keto ester products permit the synthesis of other functional groups. One of these transformations converts p-keto esters to ketones it is based on the fact that p-keto acids (not esters ) undergo decarboxylation readily (Section 19.17). Indeed, p-keto acids, and their- conesponding carboxylate anions as well, lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation. 

When the two ester groups involved in the condensation are in the same molecule, the product is a cyclic p-keto ester and the reaction is called the Dieckmann condensation.1692... 

The mechanism of the Dieckmann cyclization, shown in Figure 23.6 (p. 954), is analogous to that of the Claisen reaction. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic /S-keto ester product results. 

The intramolecular condensation of ester enolates provides efficient access to 5- and 6-member ring P-keto esters. Similar to the Claisen condensation, the Dieckmann condensation is driven to completion by deprotonation of the initially formed P-keto ester. Thus, at least one of the ester groups must have two a-hydrogens for the reaction to proceed. 

The product this time is a 3-ketoester. A suitable base would be the alkoxide that is derived from the parent alcohol of the ester, because it does not matter if the ester undergoes transesterification that is, where one alkoxy moiety is exchanged for another. Note that, instead of the anionic adduct just picking up a proton, a alkoxide anion is eliminated on the formation of the carbonyl group. If both ester groups are in the same molecule, then an internal condensation reaction is possible. This is called the Dieckmann cyclisation, and works best when the ring formed contains five, six or seven members. 

Carboxylic ester and activated N-methylene groups react under strongly basic conditions at room temperature to form a pyrrole ring, but attempts to cyclize the V-tosyl analogue of (70.1) under Dieckmann reaction conditions were unsuccessful when the -acetyl amine (70.1) was treated with sodium hydride, cyclization was achieved in good yield. 

The anion from (70.5) attacks the nitrile group and a 4-aminopyridine ring is formed in this example, the product is related to the antibacterial agent nalidixic acid. 5-Phenyl esters are useful in regioselectively directing a Dieckmann condensation of the diesters (70.6) to carbacephems. Dieckmann reactions usually requite heating but the enaminic ester (70.7) undergoes cyclization without external heat. 

A potentially valuable example of a crossed Claisen condensation was described by Tanabe and Mu-kaiyama in 1986. It arose from their earlier work on titanium(IV) ditriflate [dichlorobis(trifluorometh-anesulfonato)titanium(IV)] and triethylamine as a catalytic promoter of the simple Claisen reaction. The reaction was run in the presence of benzaldehyde, added to observe the aldol reaction, but the propionate anion added to the carbonyl group of another ester molecule in preference (equation 11). The same result was observed in a Dieckmann reaction dimethyl adipate, TiCh (OTf) (1.5 equiv.) and triethylamine... 

Cyclization by tandem Michael-Dieckmann reaction. Ring construction from compounds with juxtaposed ketone (or ester) and conjugated ester groups is made easy. It is rendered irreversible by trapping the alkoxide ion as a trimethyl-silyl ether. 

Michael addition, followed by an intramolecular aldol condensation to provide the seven-membered ring. Subsequent retro-Dieckmann reaction, dehydration, and ester saponification provide the bicyclic product in 98% yield. A related cascade reaction was recently reported by the same research group in which the reactions of various allylic halides with cyclopentanone derivatives provide seven-membered rings. ... 

The first diastereoselective synthesis of methyl (3R,7R)-jasmonate is attributed to Gerhard Quinkert. [94] In the initial step, starting from bis-(8-phenyhnen-thyl) malonate, a vinylcydopropane is constructed. After removal of the chiral auxiliary, the cyclopentanone is built up by means of a domino homo-Michael reaction / Dieckmann cydisation. Attack of dimethyl pent-2-ynylmalonate leads to inversion at the stereogenic centre at the vinyl cyclopropane. After decarboxylation, the vinyl residue is transformed into an ester group and the triple bond hydrogenated with a Lindlar catalyst. 

The mechanism involves a Michael reaction followed by a Dieckmann reaction (intramolecular Claisen), all base promoted. Loss of the ester group begins with an add-catalyzed hydrolysis, followed by decarboxylation of the resulting carboxylic acid. Finally, a Robinson annulation with methyl vinyl ketone affords the final product. 

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