Carbonyl compounds, condensation reactions Mannich reaction

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

The Mannich reaction is the condensation of an enolizable carbonyl compound with an iminium ion.180 It is usually done using formaldehyde and introduces an a-dialkylaminomethyl substituent. 

T. Akiyama, J. Takaya, H. Kagoshima, One-Pot Mannich-Type Reaction in Water HBF4 Catalyzed Condensation of Aldehydes, Amines, and Silyl Enolates for the Synthesis of (5-Amino Carbonyl Compounds Synlett. 1999,1426-1428. 

A large number of catalytic asymmetric MCR are based on deoxo-bisubstitution reactions of carbonyl compounds such as the Mannich and Strecker reactions in which an oxo-group is displaced by two new cr-bonds, one to a nitrogen atom and one to a carbon atom. Other examples of deoxo-bisubstitutions include tandem processes that involve an initial Knoevenagel condensation followed by either a nucleophilic or a cycloaddition. These processes are characterized by the conversion of a C O-K-bond into two new C-C-cr-bonds and have been termed carba-acetalizations. 

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-... 

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). 

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). 

The methylene carbon atom in a condensed 4-thiazolidinone flanked by a sulfur atom and a carbonyl group possesses enhanced nucleophilic activity and attacks an electrophilic center with ease. If the structure permits, the reaction product loses a molecule of water, and an unsaturated derivative is formed. The reaction is carried out in the presence of a base which abstracts a methylene proton. It is the anion thus formed that attacks the electrophilic center. Generally, the anion condenses with aromatic aldehydes, nitroso compounds, aryidiazonium salts, and ethyl orthoformate, as well as undergoing Vilsmeier-Haack and Mannich reactions. 

The ideal approach for the preparation of conjugated carbonyl compounds having an exo-methylene group would be via a mixed aldol condensation of an enolizable carbonyl substrate with formaldehyde as the electrophilic partner. However, formaldehyde is a very powerful electrophile and tends to react more than once with enols and enolates. This shortcoming can be circumvented by converting the formaldehyde to an iminium ion (Mannich reagent) by reaction with a secondary amine, usually dimethy-lamine, and a catalytic amount of HCl. 

Plants have taken advantage of this successful synthetic principle for their enzymatic production of isoquinoline (as well as p-carboline ) alkaloids. In the chemical laboratory, this synthetic approach has been exploited for nearly 80 years in numerous biomimetic-type syntheses. This special form of the Mannich reaction requires electron-rich aromatics, if possible with ftee phenolic oxygen functions in ortho or para positions (Scheme 9). As for the carbonyl compound, aldehydes or 1,2-dicarbonyls (and very recently 1,2,3-tricarbonyls - ) are preferred. Due to the mild physiological reaction conditions required with such ideally reactive partners (often pH = 7, room temperature, aqueous medium), this condensation was also found to play a role in human organisms, leading to endogenous mammalian alkaloids... 

Mannich reaction The condensation of CH activated compound with a primary or secondary amine and a non-enolizable carbonyl compound to afford aminoalkylated derivatives. 274... 

Amino resins (aminoplasts) are condensation products from compounds containing NH groups, which are joined by a kind of Mannich reaction to a nucleophilic component via the carbonyl atom of an aldehyde or ketone ... 

SB formation is also the first step in the Mannich reaction. In general terms, this reaction involves the formation of two covalent bonds by the condensation between an amine, a carbonyl compound, and an electronegative carbon (Figure 1.26). 

The Mannich reaction, historically, has involved the condensation of formaldehyde, a primary or secondary amine, and an enolizable carbonyl compound. The resultant P-amino-carbonyl compound, or Mannich base, requires protic solvents and high reaction temperatures for its formation. 

Sadly, this simple mechanism cannot be correct because, when the P-hydroxy ketone is made in other ways, it is not converted into Mannich product under the reaction conditions. What else can happen Amines are nucleophiles and react rapidly with carbonyl compounds in acid to give iminium ions (p. 795). It is this imini-um ion that is the real participant in the Mannich condensation reaction. Formaldehyde is more reactive than the ketone, so the iminium ion is preferentially... 

As mentioned previously in this book, the quest for sustainable, atom-economical, and environmentally friendly chemical processes is a big current issue. Besides one-pot, sequential reaction processes (generally catalyzed by either metals or enzymes), multicomponent reactions have become very important [51]. The Petasis reaction, alternatively called Petasis horono Mannich reaction, is a mUd multicomponent reaction, which was reported first by Petasis and Akritopoulou in 1993 [52]. This reaction allows the one-pot three-component condensation of an aryl- or alkylboronic acid, an amine, and an aldehyde (or generally a carbonylic compound) to generate substituted amines at room temperature (Scheme 6.38). 

Two unselective approaches to the two alkaloids are illustrated in Scheme 50. A straightforward synthesis by King relied on acid-induced intramolecular Mannich reaction of ammoketone 396, prepared from 5-aminopentanal diethyl acetal and pent-3-en-2-one, to give a mixture of ( )-394 (55%) and ( )-395 (20%) (367). The synthesis by Pilli et at. involved a one-pot trimethylsilyl triflate-catalyzed condensation between pent-3-en-2-one and the acyliminium ion derived fium JV-Boc-2-ethoxypiperidine (397) (368,369). Under the reaction conditions, the intermediate 398 underwent spontaneous V-deprotection and cyclization to give a 5.5 1 mixture of ( )-394 and ( )-395 (67%). In the same Scheme is also shown the much shorter stereoselective synthesis of ( )-394 by Beckwith et al, who used a radical-mediated cyclization on the V-acylated 2,3-dihydropyridin-4-one 399 to give the bicyclic product 400 as the sole diastereomer (91%) (370). Compound 400 was readily converted into the target alkaloid by reduction of both carbonyl groups with lithium aluminum hydride followed by reoxidation of the secondary alcohol at C-2. 

Simple tetrahydroisoquinoline alkaloids are obtained upon condensation of phenylethylamines and catecholamines with carbonyl compounds. In a subsequent Mannich-hke reaction, the biosynthetic equivalent to a Pictet-Spengler reaction, the heterocyclic ring system is established. Numerous examples of simple tetrahydroisoquinoline alkaloids have been isolated from different plant sources. Several of these tyrosine-derived secondary metabolites exhibit intriguing biological and physiological properties, due to their structural relationship to catecholamines and phenylethylamines. 

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