Mannich annulation

Methyl vinyl ketone 2 tends to polymerize, especially in the presence of a strong base the yield of annulation product is therefore often low. A methyl vinyl ketone precursor, e.g. 6, is often employed, from which the Michael acceptor 2 is generated in situ, upon treatment with a base. The quaternary ammonium salt 6 can be obtained by reaction of the tertiary amine 5, which in turn is prepared from acetone, formaldehyde and diethylamine in a Mannich reaction. 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

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]. 

These a,/l-unsaturated ketones and aldehydes are used as reactants in Michael additions (Section 1.10) and Robinson annulations (Section 2.1.4), as well as in a number of other reactions that we will encounter later. Entries 8 and 9 in Scheme 2.11 illustrate Michael reactions carried out by in situ generation of a,/ -unsaturated carbonyl compounds from Mannich bases. 

Mannich reaction of A, A -bis(methoxymethyl)diaza-18-crown-6 with 4-chloro-2-(l/f-pyrazol-3-yl)phenol gave the N-linked bis(3-(5-chloro-2-hydroxy)pyrazol-l-ylmethyl)-substituted diazacrown ether, which interacted with various metal ions and was evaluated by calorimetric titration <1999JOC8855>. Intramolecular nitrilimine cycloadditions were exploited in the preparation of a number of azacrown ethers having a medium or large ring annulated to pyrazole units <1997T3005>. 

Homoallylic amines containing an allylic hydroxy group rearrange in the presence of an aldehyde and an acid catalyst to yield 3-acylpyrrolidines. If the starting amino alcohol is cyclic, this transformation provides a pyrrolidine-annulated product, in which the initial ring is expanded by one member. The mechanism has been proposed to proceed via a tandem cationic aza-Cope rearrangement/Mannich cyclization1134. 

Kraus and Shi used condensation reactions for the assembly of precursors to the quasi-Favorskii rearrangement. Reaction of the bromoketoester 83 with ethylamine and formaldehyde gave 84, the result of a double Mannich reaction fScheme 7.22T Under acidic conditions, methyl vinyl ketone combined with 83 to give the annulation product 87. Each of these products, 84 and 87, was a good substrate for the quasi-Favorskii rearrangement. Ketone 84 reacted with the enolate of acetylcyclohexene (85) to produce 86 in 60% yield. Ketone 87,... 

The Robinson annulation is the reaction of alkali metal derivatives of cyclohexanones with a-,p>unsaturated methyl ketones to produce cycloketones and polycycloketones. The standard method for Robinson annulation is exemplified in the mechanism shown above. For the synthesis of the 1,5-diketone side chain, the enolate nucleophile reacts with a Michael acceptor this Michael acceptor is usually a substituted vinyl ketone or the parent methyl vinyl ketone (MVK), although the latter gives low yield due to its propensity to polymerize under the standard reaction conditions. To overcome the drawbacks for using MVK, Robinson, McQuillin and Du Feu introduced the Robinson-Mannich variation of the annulation reaction. This modification uses a quatemized Mannich base formed from the vinyl entity the Maimich base is made in situ and acts as a methyl vinyl ketone precursor after it is converted to its methiodides. The formed methiodides of the Mannich adduct 4-(trimethylamino-2-butanone) is condensed with sodioderivatives of ketones or with the parent ketone in the presence of sodium ethoxide. 

Polyfluoroalkyl-substituted 4-pyrones 57 react with salicylaldehydes in the presence of piperidine and p-TsOH to give a wide variety of fused 2//-chromenes 59 and 60. Compounds 59 were obtained as mixtures of the corresponding trans-and cw-isomers in variable proportions, depending on the nature of the starting materials and catalysts. This annulation proceeds by a tandem intermolecular oxa-Michael addition and subsequent intramolecular Mannich condensation [27] (Scheme 20). 

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