Aldol condensation,— SUBSTITUTED ACIDS

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

Syntheses in this category consist of intermolecular thioalkylation of 5-oxo+,5-dihydro-pyrazole-l-carbothioic acid phenyl amides 253 followed by intramolecular aldol condensation to give substituted pyrazolothiazole-type compounds 254 (Equation 111) < 1998PS119>. 

The popular methodology for the construction of carbocyclic ring consists of the intramolecular aldol condensation of properly activated monosugars. This may be exemplified by transformation of 73 into the dicarbonyl derivative 74 which, upon treatment with base (or acid), provided the desired carbocycle (Fig. 26).39 Other differently substituted derivatives were also prepared by this approach.40... 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

In the presence of strong bases, aldol condensation fails. The reason for this lies in the sluggish reactivity of anion (39 ) (Section III,B). When 39a is substituted by 3-propionyltetramic acid 39c the yield sags to 0%, obviously an expression for the high steric requirements in the transition state (87TH2). 

The dibasic side chain at position 7 can be alternatively provided by a substituted amino alkyl pyrrolidine. Preparation of that diamine in chiral form starts with the extension of the ester function in pyrrolidone (46-1) by aldol condensation with ethyl acetate (46-2). Acid hydrolysis of the (3-ketoester leads to the free acid that then decarboxylates to form an acetyl group (46-3). The carbonyl group is next converted to an amine by sequential reaction with hydroxylamine to form the oxime, followed by catalytic hydrogenation. The desired isomer (46-4) is then separated... 

Aliphatic and aromatic aldehydes condense with aliphatic and aromatic primary amines to form JV-substituted imines. The reaction is catalyzed by acids and is generally carried out by refluxing the amine and the carbonyl compound with an azeotroping agent in order to separate the water formed. The aliphatic imines (C5-C10) are obtained in good yield but are unstable and must be used directly after their distillation [2b], Tertiary aliphatic and aromatic aldehydes at room temperature react readily and nearly quantitatively with amines to give the imines without the aid of catalysts [la]. Primary aliphatic aldehydes tend to give polymeric materials with amines as a result of the ease of their aldol condensation [3]. The use of low temperatures and potassium hydroxide favors the formation of the imine product [4a, b]. Secondary aliphatic aldehydes readily form imines with amines with little or no side reactions [5]. 

Diethyl 2-oxobutanedioate undergoes an aldol condensation with aldehydes to yield the substituted dione which after hydrolysis and decarboxylation affords the 2,6-dicarboxylic acid (Scheme 16). The cyclization of this acid provides a useful synthesis of 4//-pyran-2,6-dicarboxylic acids (74ACS(B)517). It is unfortunate that attempted decarboxylation to the simple pyran fails, resulting in extensive decomposition. An earlier report (710PP243) summarizes previous work in this area and gives preparative details for the dicarboxylic acids. 

A well-known method for the synthesis of 4-quinolinecarboxylic acid derivatives involves the aldol condensation of isatins with ketones having an activated CH2 group in the presence of bases, followed by recyclization of the condensation products (or some of their subsequent transformations) to the desired compounds. Thus, the ketols 164 are formed with good yields from the ketones 163 and isatin 7 in the presence of ammonia and are transformed into 2-substituted quinolinecarboxylic acids 165 when heated in an acidic medium [23, 76],... 

The methoxy-substituted acetal C is isolated and is subjected to another two reactions (1) the acetal function is hydrolyzed under acidic conditions to provide the methoxylated aldehyde E. (2) With a catalytic amount of sodium methoxide, the methoxylated aldehyde E reacts via an Elcb elimination, which leads to the formation of the poly-unsaturated aldehyde D. The substrates A and B of the three-step reaction sequence in Figure 12.23 derive from crotonic aldehyde (E13C-CE[=CE[-CH=0) the respective methods of preparation are outlined in the figure. The final product, which is the highly unsaturated aldehyde D, displays the structure of an aldol condensation product, namely of the crotonic aldehyde mentioned above. 

B as an ester- or lactone-substituted aldehyde enolate. Such enolates undergo condensations with all kinds of aldehydes, including paraformaldehyde. An adduct E is formed initially, acy-lating itself as soon as it is heated. The reaction could proceed intramolecularly via the tetrahedral intermediate D or intermolecularly as a retro-Claisen condensation. In both cases, the result is an acyloxy-substituted ester enolate. In the example given in Figure 13.50, this is the formyloxy-substituted lactone enolate C. As in the second step of an Elcb elimination, C eliminates the sodium salt of a carboxylic acid. The a,/)-unsaturated ester (in Figure 13.50 the 0J,/3-unsaturated lactone) remains as the aldol condensation product derived from the initial ester (here, a lactone) and the added aldehyde (here, paraformaldehyde). 

The enolate A or the nitronate A, respectively, initially adds to the C=0 double bond of the aldehyde or the ketone. The primary product in both cases is an atkoxide, D, which contains a fairly strong C,H acid, namely, of an active-methylene compound or of a nitroalkane, respectively. Hence, intermediate D is protonated at the atkoxide oxygen and the C-fi atom is deprotonated to about the same extent as in the case of the respective starting materials. An OH-substituted enolate C is formed (Figures 13.52 and 13.53), which then undergoes an Elcb elimination, leading to the condensation product B. The Knoevenagel condensation and the aldol condensation have in common that both reactions consist of a sequence of an enolate hydroxy alkylation and an Elcb elimination. 

Addition of an Enolate to Ketones and Aldehydes (a Condensation) 1046 Substitution of an Enolate on an Ester (a Condensation) 1046 Base-Catalyzed Keto-EnolTautomerism 1047 Acid-Catalyzed Keto-EnolTautomerism 1047 Base-Promoted Halogenation 1054 Final Steps of the Haloform Reaction 1056 Acid-Catalyzed Alpha Halogenation 1058 Acid-Catalyzed Aldol Condensation 1063 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

Heteroatom-substituted carbohydrates are efficiently assembled by the enzymatic aldol condensation of DHAP with an appropriately appended aldehyde. Iminocyclitols that are inhibitors of glycosidases, such as deoxynojirimycin and deoxymannojirimycin, are simply prepared by condensation of azo-substituted aldehydes under the FDP protocol followed by dephosphorylation and palladium mediated reductive animation (Scheme 5.18a).39 In addition a number of polyhydroxylated pyrrolidines that are efficient glucosidase inhibitors have been synthesized by this chemo-enzymatic strategy (Scheme 5.18 ).1" 30,40 If the palladium mediated hydrogenation is done in the presence of hydrochloric acid, an amino-sugar intermediate is formed as its hydrochloride salt. Treatment with base then forms polyhydroxylated imines, instead of iminocyclitols (Scheme 5.19).41... 

Anions formed from group 6 and manganese Fischer carbene complexes undergo aldol condensations with aldehydes and ketones. Allylic carbenes exclusively react in the y position with aldehydes affording dienyl-substituted carbenes. For alkoxy-substituted carbenes, the presence of an excess Lewis acid see Lewis Acids Bases), such as boron trifluoride etherate, titanium tetrachloride, or tin tetrachloride is required for the reaction to proceed in reasonable yield. The initial aldol product can be isolated without elimination (Scheme 12). ... 

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