Addition/coupling reactions aldol condensation

The coupling of a secondary alcohol 1 with a primary alcohol 2 is achieved by the temporary removal of from each substrate which generates the ketone 3 and aldehyde 4 intermediates. A crossed aldol condensation occurs under the reaction conditions by the enolate derived from ketone 3 undergoing nucleophilic addition... 

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 Michael addition of enamines to a,p-unsaturated ketones may be coupled with intramolecular aldol condensations to produce cyclic ketones. This sequence of reactions is an alternative approach to traditional Robinson annulations (Scheme 3.22). 

Enolizable carbonyl compounds can undergo aldol condensation at temperatures in the region of 0 °C under the influence of f-BuOLi present in the reaction mixture. For this reason no large excess of the carbonyl compound should be added, while the temperature should be kept below —40 °C during the addition. The couplings are generally very fast, so that the aqueous work-up can be carried out soon after addition of the carbonyl compound. 

The reaction with oxirane, affording 0-F—C6H4—CH2CH2OH, can be carried out in a similar way and gives the alcohol in a reasonable (about 70%) yield. Oxirane is added in an excess of 30 %. In the absence of HMPT the reaction is very slow. Couplings with aldehydes and ketones or thiolation with elemental sulfur have to be carried out with the lithium compound, which can be prepared as indicated, or by addition of a solution of anhydrous LiBr in THF to the solution of the potassium compound. f-BuOLi present in the solution may give rise to aldol condensation of enolizable aldehydes and ketones, particularly at temperatures in the region of 0 °C. Therefore, the use of an excess of the aldehyde or ketone should be avoided. 

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

The aldol reaction is one of the most important ways to construct carbon-carbon bonds in organic synthesis. Nature itself seems to prefer this reaction in its biosynthetic processes, for example, in the prebiotic formation of saccharides [1]. Strictly speaking, the aldol reaction is the self-coupling of an aldehyde, having at least one active hydrogen in the a-position, to give a p-hydroxyaldehyde called an aldol (aldol addition), which sometimes dehydrates (aldol condensation). 

A Michael reaction coupled with aldol-type condensation has been used in the one-pot synthesis of allylrethrone (Scheme 7.7), an important component of an insecticidal pyrethroid [32]. The conjugative addition of 5-nitro-l-pentene to methyl vinyl ketone is catalyzed by AI2O3 and occurs in the absence of solvent. An intramolecular aldol-type condensation is then carried out in alkaline aqueous medium after the conversion of the nitro group into a carbonyl by the Nef reaction. 

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

Mukund Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2004,126,718) a powerful three-component coupling, combining an a,(5-unsaturated amide 9, a hydroxylamine 10, and an aldehyde 11. The hydroxylamine condenses with the aldehyde to give the nitrone, which then adds in a dipolar sense to the unsaturated ester. The reaction proceeds with high diastereocontrol, and the absolute configuration is set by the chiral Cu catalyst. As the amide 9 can be prepared by condensation of a phosphonacetate with another aldehyde, the product 12 can be seen as the product of a four-component coupling, chirally-controlled aldol addition and Mannich condensation on a starting acetamide. 

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