Formaldehyde imines Mannich reaction

The mechanism involves the preliminary formation of an imine salt from the amine and formaldehyde. The amine is nucleophilic and attacks the more electrophilic of the two carbonyl compounds available. That is, of course, formaldehyde. No acid is needed for this addition step, but acid-catalysed dehydration of the addition product gives the imine salt. In the normal Mannich reaction, this is just an intermediate but it is quite stable and the corresponding iodide is sold as Eschenmoser s salt for use in Mannich reactions. 

Whereas the imines formed with aromatic aldehydes are relatively stable, those formed from aliphatic aldehydes are often unstable and undergo further reaction. If the reaction with formaldehyde is carried out with the salt of a primary or secondary amine and a ketone containing an acidic hydrogen, a new C-C bond is formed. This reaction, known as the Mannich reaction (Scheme 2.35), has played a useful role in many syntheses. 

The classical Mannich reaction converts phenols to aminomethylated phenols. The reaction involves the addition of phenols to C=N bonds of imines or iminium salts formed from formaldehyde and primary or secondary amines, respectively . Recent modifications employ the reaction of an aminal in the presence of SO3, which gives a sulfonate ester, followed by o-aminomethylation (equation Sc(OTf)3 catalyzed... 

The imine and iminium functional groupings are, of course, the nitrogen equivalents of carbonyl and O-protonated carbonyl groups, and their reactivity is analogous. The Mannich reaction of pyrrole produces dialkylaminomethyl derivatives, the iminium electrophile being generated in situ from formaldehyde, dialkylamine and acetic acid. There are only a few examples of the reactions of imines themselves with pyrroles the condensation of 1-pyrroline with pyrrole as reactant and solvent is one such example. N-Tosyl-imines react with pyrrole with Cu(OTf>2 as catalyst. ... 

The Mannich reaction is the prototype of carbon-carbon bond forming reactions that involve the addition of resonance-stabilized carbon nucleophiles to iminium salts and imines. In its original and most widely recognized form, the Mannich reaction consists of three components (i) ammonia, a primary amine, or a secondary amine (ii) a nonenolizable aldehyde, usually formaldehyde and (iii) an active... 

Benzylideneanilines have been added across 2,3-dihydrofurans to produce bicyclic azetidines regio- and stereoselectively a zwitterionic mechanism is proposed. An extensive range of reaction parameters have been calculated for the Mannich reaction of benzoxazole with formaldehyde/dimethylamine. A molybdenum bis(imide) has been used to catalyse C=N bond formation in imine-imine metathesis reactions of synthetic interest the approach has been extended to alkylidene-imine, imide-imine, and imide-imide metatheses. 1-Substituted 1-phenyl-... 

Imines are generally less electrophilic than the corresponding aldehyde but this diminished level of activity can be countered by suitable activation with Lewis acids. Formaldehyde imines are generally stable only at low temperatures and are best formed in situ. However, there are exceptions like Eschenmoser s salt 20. This methylene iminium salt is a relatively stable solid that is now commercially available. The utility of this reagent was illustrated in the Mannich reaction of corrin 19 with 20 to generated 21. 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

In Summary Condensation of aldehydes (e.g., formaldehyde) with amines furnishes imin-ium ions, which are electrophihc and may be attacked by the enols of ketones (or other aldehydes) in the Mannich reaction. The products are j8-aminocarbonyl compounds. 

When the enone required for such reactions is unstable, it can be produced in situ by amine elimination from a p-amino carbonyl compound, prepared in turn from an enolate and an imine of formaldehyde in the Mannich reaction. 

Phosphorous acid has also been of use for additions to imines. Originally investigated by Moedritzer and Irani,241 who developed a Mannich-type procedure for the preparation of phosphorus-centered species, the approach was found later to be useful for both primary and secondary amines in reaction with formaldehyde and phosphorous acid. The approach was later used for the preparation of a cationic exchange resin using a polymer substrate.242... 

Fig. 10.3-5 Tyrosine modification using a when proteins are treated alone with either three component Mannich-type reaction. component, (b) The reaction conversion is (a) Aldehydes and anilines condense to listed for a number of anilines and aliphatic form imines in situ, which react with tyrosine amines using a-chymotrypsinogen A as the residues through an electrophilic aromatic substrate and formaldehyde as the aldehyde substitution reaction. No reaction occurs component.

Quite recently, benzoylhydrazones derived from a-functionalized aldehydes and formaldehyde have been prepared as stable equivalent of unstable imines, and successftdly used in Mannich-type reactions (Manabe et al. 2000). 

Compounds capable of forming an enol react with imines from formaldehyde and a primary or secondary amine to yield /3-aminoalkyl carbonyl compounds called Mannich bases. The following reaction of acetone, formaldehyde, and diethylamine is an example ... 

Simple imines are generally unreactive toward dienes without activation. In 1985, Grieco and Larson [1] first reported that simple unactivated iminium ions, generated in situ under Mannich-like conditions, react with a variety of dienes in water to effect an exceptionally mild and convenient cyclocondensation reaction. Water as a solvent is particularly suited to using commercially available 37% aqueous formaldehyde in combination with an amine hydrochloride to form the incipient protonated imine heterodienophile. 

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