Carbonyl condensation reactions Dieckmann reaction

The Claisen reaction is a carbonyl condensation that occurs between two ester components and gives a /3-keto ester product. Mixed Claisen condensations between two different esters are successful only when one of the two partners has no acidic a hydrogens (ethyl benzoate and ethyl formate, for instance) and thus can function only as the acceptor partner. Intramolecular Claisen condensations, called Dieckmann cyclization reactions, provide excellent syntheses of five- and six-membered cyclic /3-keto esters starting from 1,6- and 1,7-diesters. 

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. 

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... 

The mechanism of the Dieckmaim condensation is the same as the mechanism of the Claisen condensation. The only difference between the two reactions is that the attacking enolate and the carbonyl group undergoing nucleophilic attack are in different molecules in the Claisen condensation, but are in the same molecule in the Dieckmaim condensation. The Dieckmann condensation, like the Claisen condensation, is driven... 

Carbanions frequently add to the carbonyl double bond. The aldol reaction, Claisen reaction, Dieckmann reaction, Michael reaction, and Knoevenagel condensation are familiar examples of carbanions (as enolates) undergoing nucleophilic addition to carbon-oxygen double bonds. 

To most organic chemists the term Claisen condensation implies the self-condensation of esters in the presence of sodium ethoxide to give 0-ketoesters. A Dieckmann condensation is a special Claisen condensation in which an ester of a dibasic acid undergoes intramolecular condensation to produce a cyclic jS-ketoester. From the point of view of mechanism, however, this idea of a Claisen condensation is perhaps unnecessarily limited, for there are a number of extremely closely related reactions which involve compounds other than esters, and bases other than sodium ethoxide. In all these transformations, the essential feature of the reaction is the addition of a carbanion to a carbonyl group, followed by the loss of a negative ion from the seat of reaction. 

The additional carbon atom required for building the five-membered ring D is then added by means of methyl-magnesium bromide (16-4). The ester at future C15 is reduced to a carbinol by reaction with lithium aluminum hydride. Swern oxidation (dimethyl sulfoxide and oxalyl chloride) next serves to oxidize each of the two resulting hydroxyl groups to carbonyl functions (16-5). Dieckmann-like base-catalyzed condensation then closes the five-membered ring... 

In an aldol addition, the enolate of an aldehyde or a ketone reacts with the carbonyl carbon of a second molecule of aldehyde or ketone, forming a j8-hydroxyaldehyde or a jS-hydroxyketone. The new C—C bond forms between the a-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. The product of an aldol addition can be dehydrated to give an aldol condensation product. In a Claisen condensation, the enolate of an ester reacts with a second molecule of ester, eliminating an OR group to form a j8-keto ester. A Dieckmann condensation is an intramolecular Claisen condensation. A Robinson annulation is a ring-forming reaction in which a Michael reaction and an intramolecular aldol addition occur sequentially. 

In the Dieckmann condensation certain esters having hydrogen on the a-carbon atom which is activated (generally by a carbonyl group) undergo intramolecular cyclization. These reactions may be illustrated by the formation of a-carbethoxy-cyclopentanone from diethyl adipate. 

The synthesis scheme is described in two process patents [70] Dieckmann condensation applied to ethyl adipate leads to the salt of 2-ethoxycarbonylcyclopenta-none (Scheme 17.12). From this compound, methylation at position 2 followed by a rearrangement under basic medium brings the methyl group to position 5. The salt obtained is directly benzylated with 4-chlorobenzyl chloride. A second methylation then occurs directly at position 5 and a subsequent decarboxylation allows access to the key carbonyl cyclopentanone with all the required substituents present. The last step consists of a one-pot Corey-Chaykovsky epoxidation reaction in which are successively added to the triazolyl sodium formed in situ, the cyclopentanone and the trimethylsulfoxonium bromide. 

The reductive coupling of carbonyl compounds with active metals (Na, Mg, Al) yields pinacols. An electron transfer from the metal surface to the carbonyl oxygen (ketyl formation), a soft-soft interaction, is undoubtedly involved. The conversion of esters to acyloins (22, 23) on the surface of metallic sodium is well known. Here the enediolate products can be trapped in situ by Me3SiCl (24). The chlorosilane does not interfere with the coupling, yet it effectively removes the alkoxide ions and neutralizes the enediolate ions immediately on formation. The elimination of RO is imperative, for otherwise Claisen or Dieckmann condensations would compete with the normal course of reaction. These complicating processes require a hard base (e.g. RO ) to abstract a proton from the starting esters, whereas the desired coupling is accomplished by a soft base which is the electrons on the metal surface. 

Addition of enolate anions derived from aldehydes or ketones (aldol reactions) and esters (Claisen and Dieckmann condensations) to the carbonyl groups of other aldehydes, ketones, or esters. 

Note that aldol, Claisen, and Dieckmann condensations all give primary products with oxygens in a 1,3 relationship. The Michael reaction with enolate anions gives products with oxygens in a 1,5 relationship. These relationships are a consequence of the polarization of the reagents. In aldol, Claisen, and Dieckmann condensations, the carbonyl carbon is positive and the a-position is negative. 

Claisen and Dieckmann condensations are reversible. The driving force is the deprotonation of the alpha hydrogen in the product between the two carbonyls. This deprotonation prevents the reaction from reversing, pulling the product out of the equilbrium. 

Dieckmann-type reaction mechanism and not through a Stobbe-type reaction mechanism, as is the case in the Hinsberg reaction with oc-diketones. The usefulness of the Gewald reaction for the synthesis of 2-amino-3-carbonyl-substituted thiophens, important building-blocks for the synthesis of fused thiophens, has clearly been demonstrated. From the condensation products of cycloalkanones and nitriles (1), the thiophens (2) were obtained through the reaction with sulphur in the presence of diethylamine. Similarly, from the dithiacyclo-octane derivative (3), the thiophen (4) was prepared. In connection with the synthesis of psychophar-maca of the diazepine type, several substituted 2-amino-3-benzoylthiophens (5) were prepared through the reaction of phenacyl cyanides with aldehydes... 

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