Ketones, condensation with aldehydes

Claisen-Schmidt reaction. Aromatic aldehydes condense with aliphatic or mixed alkyl-aryl ketones in the presence of aqueous alkali to form ap-unsaturated ketones ... 

Pyruvic Acid Compounds.—Lubrzynska and Smedley have recently shown that a number of aldehydes such as heliotropin, anisic aldehyde, benzaldehyde, and cinnamic aldehyde, condense with pyruvic acid in slightly alkaline solution, with the formation of )8-unsaturated-a-ketonic acids. For example, if heliotropin and pyruvic acid in alkaline solution be left standing for about eight days at ordinary temperature, dihydroxy-methylene-benzal-pyruvic acid is formed. This body forms yellow needles, melting at 163° Similarly, anisic aldehyde yields methoxy-benzal-pyruvic acid, melting at 130° and cinnamic aldehyde yields cinnamal-pyruvic acid, melting at 73°. 

Aldehydes condense with compounds containing a reactive methyl-or methylene-group to form unsaturated ketones, e.g. 

Aldehydes condense with DISN to give 2-alkylimidazoles, but in low yield (73USP37099(X)). A related reaction with ketones produces 2,2-dialkyl-4,5-dicyano-2//-imidazoles. When one alkyl group is methyl and the other is a... 

A retrosynthetic analysis of a,/J-unsaturated ketones leading to various methods of synthesis is outlined in Section 5.18.2, p. 798. These methods are equally applicable to aromatic aldehydes. Aromatic aldehydes condense with aliphatic or mixed alkyl aryl ketones in the presence of aqueous alkali to form a,[i-unsaturated ketones (the Claisen-Schmidt reaction). 

The reaction of aliphatic, alicyclic, and aromatic aldehydes and ketones with cyanoacetic ester, NCCHjCOjCjH, is general. The products are 0L,/3-olefinic cyanoacetates. The aldehydes are condensed with the ester in the presence of amines or with sodium cyanoacetate in the presence of sodium hydroxide, Similarly, cyanoacetic ester is condensed with ketones by catalysts such as acetamide or the acetates... 

Ethyl cyanoacetate condenses with ketones and ammonia in absolute ethanol at 0-5° to give 44-73% yields of cyclic dicyanoimides. Endocyclic ketones may be used, giving imides in which the two radicals are p>art of an alicyclic ring. The imides are hydrolyzed and decarboxylated in almost theoretical yields to yS,/S-disubstituted glutaric acids. A similar reaction takes place between aldehydes or ketones and cyanoacetamide, NCCHjCONHj, in the presence of piperidine or potassium hydroxide. When aldehydes are used, the condensation products are dicyanoamides, RCH[CH(CN)CONHj]j, rather than cyclic imides. 

The isolation of the initial aldol products from the condensation of the enolates of carbene complexes and carbonyl compounds is possible if the carbonyl compound is pretreated with a Lewis acid. As indicated in equation (9), the scope of the aldol reaction can also be extended to ketones and enolizable aldehydes by this procedure. The condensations with ketones were most successful when boron trifluoride etherate was employed, and for aldehydes, the Lewis acid of choice is titanium tetrachloride. The carbonyl compound is pretreated with a stoichiometric amount of the Lewis acid and to this is added a solution of the anion generated from the caibene complex. An excess of the carbonyl-Lewis acid complex (2-10 equiv.) is employed however, above 2 equiv. only small improvements in the overall yield are realized. 

Aryl aldehydes condense with aliphatic aldehydes in the presence of benzoylfor-mate decarboxylase and thiamin diphosphate to give an a-hydroxy ketone with god enantioselectivity. ° ... 

Phosphonate carbanions are more nucleophilic than phosphonium ylides. Thus, they can be used in condensations with ketones as well as with aldehydes under mild conditions. 

Reaction of the tertiariz-butylimine from acetaldehyde with (Et0)2 POCl, in the presence of two equivalents of base gives the corresponding ylide. This gives good yields of substituted acroleins on condensation with ketones and aldehydes. " ... 

The methylene group of malonic or cyanoacetic acid is sufficiently reactive to condense under mild conditions with aliphatic or aromatic aldehydes or with ketones. Initially such reactions were carried out in the same way as the Perkin reaction, in acetic acid solution or in the presence of acetic anhydride however, use of acetic anhydride is unnecessary. 

Heterocyclic aldehydes such as 6-quinolinecarbaldehyde936 and 2-quinoline-carbaldehyde937 can also be condensed with ketones and esters. 

The substituent effect on the enolization of carbonyl compounds may be analyzed in the HSAB context. When X of (5) is hydrogen, C-1 is softened and enolization is favored. The C-1 of the enol form (6) is probably softer since it is doubly bonded to another carbon instead of to oxygen as in the keto form. Aldol condensation (15) proceeds much more readily with aldehydes than with ketones, and enolization almost invariably preludes C-C bond formation (16). When X = Cl, OH, OR, and other electronegative groups, C-1 becomes harder and enolization is thereby discouraged. 

Formation of Hydrazones. Most of the chemistry developed with TPSH has been done with the corresponding hydrazones obtained by condensation with ketones and aldehydes. The condensation usually takes place by mixing equimolar quantities of TPSH and the carbonyl compound in a protic solvent such as ethanol or methanol with a catalytic amount of acid at room temperature. Different solvents and acid-free conditions have been employed as well (eq 17). The hydrazones are stable and can be isolated by filtration or flash chromatography. 

Dianions derived from phosphonate (150) undergo clean condensations with aldehydes to give the unsaturated keto-esters (151) in 60— 96% yields. It is perhaps surprising that these very useful compounds have not been prepared by this route before. Contemporaneously, the synthesis of keto-esters (151) via the diphenylphosphine oxide corresponding to (150) has also been reported. In this case, yields are much the same and, as above, condensations with aldehydes give exclusively (H)-(151). In both cases, condensations with ketones give ( )/(Z) mixtures. The homologous phosphonates (152) can be obtained by reactions between a-diazophosphonates and diketen followed by methanolysis. ... 

The most efficient variant of this combination is based on reaction of an enolizable ketone with a non-enolizable aldehyde, so that self-condensation of the latter cannot occur. Several examples of this type of combination in aldol reactions are given in Scheme 1.2. Usually in situ elimination occurs, so a,j5-unsaturated ketones result, in particular when aromatic aldehydes are condensed with ketones ( Claisen-Schmidt reaction ) [18-21]. 

Stereochemistry in the Knoevenagel condensation is driven by sterics, with the thermodynamic products being formed. If the two EWGs in the active methylene compound are different in size, excellent selectivity can be obtained in the condensation with aldehydes, or with ketones that are also sufficiently different on each side. ... 

The precursor (121) for the A-ring was prepared in three steps from aldehyde (120). This compound was condensed with ketone (119) in a Borsche modification of the Friedlander reaction to give tetracyclic quinoline (122) (Scheme 18). Selective cleavage of the A-ring p-methoxybenzyl protecting group allowed further transformation to nitro compound (123). 

Carbonyl Condensations. Bis- or tris-TMS ketenimines condense with ketones, mediated by MgBr2, to produce an intermediate that loses hexamethylsiloxane, affording 2-alkenenitriles in high yield with high ( ) selectivity (eq 16). MgBr2 also enables the use of very mild bases like Triethylamine in Homer-Wadsworth-Emmons reactions, enabling the synthesis of unsaturated esters from aldehydes or ketones without the need for strongly basic conditions (eq 17). ... 

Claisen reaction Condensation of an aldehyde with another aldehyde or a ketone in the presence of sodium hydroxide with the elimination of water. Thus benzaldehyde and methanal give cinnamic aldehyde, PhCH CH-CHO. 

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