Amine-Catalyzed Aldol Condensation Reactions

SECTION 2.2. AMINE-CATALYZED ALDOL CONDENSATION REACTIONS 

A number of preparatively useful reactions are variants of the mechanistic pattern established by the aldol condensation. One important group is a family of condensations that effect transformations quite similar to the aldol, but that are particularly effectively catalyzed by amines or buffer systems containing amines and the corresponding conjugate acid. These amine-catalyzed reactions are often referred to as Knoevenagel condensations.  

In several cases, it has been established that the amines do not function as simple bases but instead are involved in prior reaction with the carbonyl compounds as well. Kinetic evidence in support of such a mechanism in the condensation of aromatic aldehydes with nitromethane has been reported. The fact that such condensations are often most effectively catalyzed when a weak acid is present in addition to the amine suggests that amines do not function as simple base catalysts. The reactive electrophile is probably the protonated form of the imine formed by condensation of the carbonyl compound and the amine. This iminium ion will be considerably more electrophilic than a carbonyl group because of the positive charge. 

CHAPTER 2 REACTIONS OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS 

A closely related variation of the reaction uses cyanoacetic acid or malonic acid, as opposed to the corresponding esters, as the potential nucleophile. The mechanism of the addition phase of the reaction under these circumstances is similar to the previously discussed cases. The addition intermediates, however, are susceptible to decarboxylation. In many instances, the decarboxylation and elimination phases may occur as a single concerted process. Many of the decarboxylative 

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Antibody Catalysis. Recent advances in biocatalysis have led to the generation of catalytic antibodies exhibiting aldolase activity by Lemer and Barbas. The antibody-catalyzed aldol addition reactions display remarkable enantioselectivity and substrate scope [18]. The requisite antibodies were produced through the process of reactive immunization wherein antibodies were raised against a [Tdiketone hapten. During the selection process, the presence of a suitably oriented lysine leads to the condensation of the -amine with the hapten. The formation of enaminone at the active site results in a molecular imprint that leads to the production of antibodies that function as aldol catalysts via a lysine-dependent class I aldolase mechanism (Eq. 8B2.12). 

Reymond and Chen88 have investigated the same set of antibodies for their ability to catalyze bimolecular aldol condensation reactions. The antibodies were assayed individually at pH 8.0 for the formation of aldol 111 from aldehyde 109 and acetone. None catalyzed the direct reaction, but in the presence of amine 110 three anti-52a and three anti-52b antibodies showed modest activity. In analogy with natural type I aldolase enzymes, the reaction is believed to occur by formation of an enamine from acetone and the amine, followed by rate-determining condensation of the enamine with the aldehyde. As in the previous example, the catalyst, which was characterized in detail, is not very efficient in absolute terms ( cat = 3 x 10-6 s 1 for the anti-52b antibody 72D4), but it is approximately 600 times more effective than amine alone. Moreover, the reactions with the antibody are stereoselective The enamine adds only to the si face of the aldehyde to give... 

Aldol condensation reactions are catalyzed by amines and the active sites of many aldolases contain an essential lysine residue. Using a strategy of reactive immunization with a 1,3-diketone (18 in Fig. 5.8), Wagner et al. were able to generate antibodies with aldolase activity. These were shown to possess a highly reactive lysine residue in... 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

Although aminocatalysis of the aldol reaction via enamine intermediates is an important enzymatic strategy and several bioorganic studies of the subject have appeared, applications in preparative organic synthesis, particularly in intermolecular aldol addition reactions, have been published only sporadically. Despite the often-used Mukaiyama-aldol reaction of enol ethers and Stork s vell-developed enamine chemistry [37, 38], aldolizations of preformed enamines are rare. One report describes Le vis acid-catalyzed aldolizations of preformed enamines vith aldehydes that furnish aldol addition products [39]. Aldol condensation reactions of preformed enamines vith aldehydes have also been described [40]. Only enamine-catalytic aldolizations, vhich are primary and secondary amine-catalyzed aldol reactions, vill be discussed in this chapter, ho vever. 

Despite these mechanistic and theoretical studies, intermolecular amine-catalyzed aldolizations have only rarely been used on a preparative scale. A few note vorthy exceptions in vhich aldehydes are used as donors are sho vn in Scheme 4.6 [51-55]. These reactions are often performed neat or in the presence of small amounts of an organic solvent. The catalyst usually used is either a primary or secondary amine, a combination of an amine vith a carboxylic acid, or simply an amino acid. These catalyst systems have previously been used in the Knoevenagel condensation and it is apparent that synthetic amine-catalyzed aldolizations originate from Knoevenagel s chemistry [56]. 

The Knoevenagel reaction is a base-catalyzed aldol-type reaction that can occur through two possible mechanisms, depending on the type of base used. When Emil Knoevenagel made his initial discovery of this reaction, it was already known that benzaldehyde could condense with two equivalents of piperidine to provide the benzylidine bispiperidine aminal 1 Therefore, he proposed the intermediacy of an aminal (or imine) in the condensation. 

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]. 

There also exists an acid-catalyzed regioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291 f.). The condensation of secondary amines with aldehydes yields immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CH2-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,/3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercuryfll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

Cr3+ can also be integrated into the structures of layered double hydroxides. A mixed oxide, prepared by calcination of ZnCr-LDH-CCh, was used in combination with t-BuOOH for the ketonization of alkyl and of benzyl pyridines and for the oxidation of benzyl amines to give Schiff bases (67,68). In contrast to MgAl-LDHs, for example, these materials display hardly any basicity so that base-catalyzed side reactions such as aldol condensations are avoided. 

Also, the primary amine moities of polar lipids catalyze the aldol condensation of Cm-Cig aldehydes resulting from plasmalogen hydrolysis, thus forming a,3-unsaturated aldehydes (l2t). Phosphatidyl ethanolamine reacted with propanal and n-hexanal forming phosphatidyl l-(2-hydroxyethyl)-2-ethyl-3,5-dimethyl pyridinium, and phosphatidyl-1-(2-hydroxy ethyl)-2-hexyl-3,5-dipentyl pyridinium, respectively (125). The peridinium ring is formed by the reaction between one mole of amino-N of phosphatidyl ethanolamine and three moles of n-alkanals. The same reaction took place in the synthesis of substituted pyridines by condensation of carbonyl compounds with ammonia (126, 127). 

The Michael reaction in combination with an aldol condensation provides a useful method for the construction of six-membered rings in a process termed the Robinson annulation. In the following example a tertiary amine is used as the base to catalyze the conjugate addition. Then, treatment with sodium hydroxide causes an intramolecular aldol condensation to occur. 

Aldol condensation of the intermediate aldehyde might be catalyzed by amines or basic sites on the catalyst surface. The unsaturated dimer and oligomers are strongly adsorbed by the metal surface and block the active sites. The usual concentration of hydrogen in the reaction mixture is ca 0.1-2 mol (mol alcohol) ... 

Asymmetric aldolization of a-isocyanoacetamide and fluorinated benzaldehydes has been realized with a gold(I) salt and a ferrocenyl amine-phosphine ligand. (Salen)-Ti complexes serve well in catalyzing the condensation of diketene with aldehydes. " A camphor lactam is an adequate chiral auxiliary as its derived imide undergoes asymmetric aldol reactions. 

It is interesting that the condensation between electron-rich phenol, amine, and a chiral a -A, A -dibenzylamino aldehyde has been reported to be temperature sensitive, with high syn selectivity at high reaction temperatures while high anti selectivity is observed at low reaction temperatures. Similar to the Aldol Condensation, the Mannich reaction can be promoted or catalyzed by either acid or base. Furthermore, different protic acids or Lewis acid alone or in combination with a different chiral ligand or auxiliary group is used to enhance the stereoselectivity of the Mannich reaction, such as proline, (,S )-amino sulfonamide, BINOL phosphate," At-spiro chiral quaternary ammonium bromide, and dodecylbenzenesulfonic acid" as well as Lewis acids, such as Cu(OAc)2, CuC104, " Cu(OTf)2-chiral diamine complexes,... 

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