Aldol and Mannich condensations

As can be seen, the same four classical condensations which were mentioned before, are again present i. e., Claisen, aldol, and Mannich condensations and the Michael addition. 

Some chiral phase-transfer catalysts can also promote enantioselective aldol and Mannich condensations of glycine imine donors with aldehyde and imine acceptors. These reactions provide important tools for the asymmetric constmction of P-hydroxy-a-amino acid and a,p-diamino acid derivatives, which are extremely interesting chiral units in the synthesis of pharmaceutical and natural products. For... 

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. 

LLC networks containing catalytic headgroups have also been shown to be useful for heterogeneous Lewis acid catalysis. The Sc(III)-exchanged cross-linked Hu phase of a taper-shaped sulfonate-functionalized LLC monomer has been shown to be able to catalyze the Mukaiyama aldol and Mannich reactions [115] with enhanced diastereoselectivity. This Sc(III)-functionalized Hu network affords condensation products with syn-to-anti diastereoselectivity ratios of 2-to-l, whereas Sc(III) catalysts in solution or supported on amorphous polymers show no reaction diastereoselectivity at all. 

In principle, the synthesis of a consonant molecule or a bifunctional relationship within a more complex polyfunctional molecule, does not offer too many difficulties. In fact, all the classical synthetic methods of carbon-carbon bond formation that utilise reactions which are essentially reversible, lead to consonant relationships. For instance, the book by H.O. House "Modem Synthetic Reactions" [22], after dealing, for almost 500 pages, with functional group manipulations, devotes the last 350 pages to carbon-carbon bond formation, all of which lead to consonant relationships. These methods can, actually, be reduced to the following four classical condensations (and their variants) Claisen condensation, aldol condensation, Mannich condensation and Michael addition (Table 2.5). 

Related to their application in synthesis, protic ILs have been used in C-C bond-forming reactions (Knoevenagel condensations, Diels Alder reactions, alkylation and Henry reactions, aldol condensations and Mannich reactions)... 

Control of the pH is also of importance for the Mannich-based bispidine synthesis. Formation of an aldol product competes with the Mannich condensation in the basic pH region. It is for this reason that, in some cases, the reaction is sensitive to the order in which the reactants are added to the reaction mixture. It is possible to add the aldehyde and amine components one after another to a solution of the CH-acidic compound, but sometimes the aldol reaction can be disfavored by changing the order. This allows the imminium ion to be formed in advance. The precursors of 45 and 46 have been prepared by this method. In some cases, it has been useful to use a protonated amine component as the acetate salt (e.g., 49 or precursors for 44, 47, and 48), as the chloride salt (e.g., 11) or to carry out the reaction in acetic acid. Aromatic amines (e.g., aniline) give rise to para-substituted aromatic amines if the solution is not approximately neutral. In a very elegant procedure, a condensate of formaldehyde and aniline, which is the trimeric methyleneaniline, was prepared separately, and treated in the Mannich reaction with dimethyl acetonedicarboxylate and formaldehyde to yield the 3,7-diphenylbispidone... 

The approximately 80 known pyrrolidine alkaloids possess a 5-membered nitrogen-containing ring (Massiot and Delaude, 1986 Binder, 1993). Several subgroups of pyrrolidine alkaloids arise by condensation of these units with other molecules, Pyrrolidine bases usually are modified by additional Schiff-base formation, Mannich condensation, and aldol-type processes to yield other alkaloids of tiiis general class. For example, condensation of pyrrolidine derivatives with nicotinic acid is involved in the formation of pyridine alkaloids such as nicotine see Chapter 28). Pyrrolidine units react with acetyl- or malonyl-CoA and condense via a Mannich condensation to form compounds such as hygrine and cuscohygrine and tropane alkaloids see below). 

In these first experiments, starting from several aldehyde acceptor molecules 2a-c, the Mannich products 8a-c were obtained in moderate to good yields and generally high enantioselectivity after 12 h of stirring in a mixture of acetone and DMSO (Scheme 5.2). Some side-products were also formed due to competing aldol reactions and subsequent condensations thereby accounting for the somewhat lower yields. 

Sc(0Tf)3 as a water-compatible Lewis acid catalyst has been reported to exhibit particularly high catalytic performances for a series of Lewis acid-catalyzed reactions the Friedel-Crafts alkylation, allylation reactions, Mukaiyama aldol condensation, and Mannich-type reaction [3,49,50]. The same metal triflate was reported to show catalytic activity for other Lewis acid-catalyzed reactions with carhonyl compounds (Equation (8.23)) in water. Its activity was indicated to he far superior to the other metal triflates, which was suggested as an indication that the high stahiUty of metal triflate-carhonyl compound complexes causes high catalytic performance for these reactions [7]. 

Since aliphatic nitroalkanes are active methylene compounds, these may be used as starting materials for the preparation of more complex products by typical reactions of methylene compounds such as alkylations, aldol condensations, Michael condensations, and Mannich reactions. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

When performing a Mannich reaction in its initial three-component design, the selectivity is sometimes difficult to obtain due to the competition with the side processes, primarily the auto-aldol condensation [52, 80], A common solution for this problem is the pre-formation of an imine or the enolate, or both and thus the sequential (indirect) performance of the reaction (Scheme 35) [52],... 

After the initially performed aldol condensations and the process optimisation, the scope of the reaction was further extended to an enantiomeric Mannich reaction. The authors started from A-PMP-protected ot-imino ethyl glyoxylate and cyclohexanone in the presence of 5% catalyst loading. In 10 min at 60°C, the conversions were complete and the p-aminoketone was obtained in 91% yield and >95% ee after purification on column. 

Acetyl thiadiazole also displays enhanced reactivity in both the carbonyl and the methyl groups and enters the aldol condensation, the Mannich reaction, cyanoethylation reaction, the Willgerodt... 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

Thus, IQ may arise from creatinine, 2-methylpyridine and formaldehyde or a related Schiff base, formed from glycine through Strecker degradation. The initial step may be a Mannich reaction or an aldol condensation. By analogy MelQ may arise from creatinine, alanine and 2-methylpyridine, and MelQx from creatinine, glycine and 2,5-dimethylpyrazine according to the scheme in Figure 1. 

By way of Mannich reaction (step 1) and /1-elimination (step 2), the transformations shown in Figures 12.14 and 12.15 demonstrate how an aldol condensation (for the term see Section 13.4.1) can be conducted under acidic conditions as well. Both the enamine reaction in Figure 12.18 and the enol ether reaction in Figure 12.23 illustrate the same thing differently. Many aldol condensations, however, start from carbonyl compounds only and proceed under basic conditions. They follow a totally different mechanism (Section 13.4.1). 

Earlier syntheses of arylquinolizidine alkaloids mainly utilized the pelletierine condensation to construct the basic skeleton, 4-aryl-2-quinolizidinone (11) (Scheme 1). Two mechanistic pathways, involving (a) initial aldol condensation of pelletierine (8) with an aromatic aldehyde followed by intramolecular Michael-type addition of the resulting enone 9 (6, 7) and (b) a Mannich-type reaction through 10 (8, 9), were proposed without any experimental evidence. Preparation and cyclization studies of the intermediate 9, however, gave conclusive evidence to show that the pelletierine condensation proceeded through pathway a (10). 

The total synthesis was achieved in 1954 by Woodward and his collaborators (156). Before this, various unsuccessful attempts had been made to make a start toward a synthesis of strychnine (179, 180, 181, 182,) but these are now of little interest, with the exception of Robinson s idea (182) to emulate the postulated biosynthesis by attempting to synthesize the dialdehyde CCXVI, which then might be induced to cyclize by a combination of Mannich and aldol type condensations to the Wieland-Gumlich aldehyde (LV) the synthesis of CCXVI unfortunately was not realized. Much more recently, however, this idea has been used by van Tamelen et al. (184), who successfully synthesized the dialdehyde CCXVII and converted it in aqueous acetic acid-sodium... 

Various condensations of 3-acetyl-l,2,5-thiadiazole (83) have been carried out which indicate a high degree of reactivity of both the carbonyl and the methyl group. The reactions investigated include the aldol condensation of 88, the Mannich reaction to 89, triscyano-ethylation to 90, and the Willgerodt-Kindler reaction to 91. The reactions proceeded under mild conditions and the normal products were obtained in good yield in each case. ... 

The Michael addition represents an extremely efficient synthetic method for achieving chain elongation by adding a three (or more) carbon fragment electrophile to a nucleophilic moiety. Notice that the typical Michael electrophiles (e.g. 90) are products of condensation of carbonyl compounds and can be easily formed via the aldol-like condensation, the Wittig reaction (with ylides like 81), the Perkin reaction, or the Mannich reaction (see below). 

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