Further advances in the chemistry of mannich bases

Begehrte Bausteine fur die Synthese von Wirk- oder Naturstoffen sind Mannich-Basen und deren Derivate. Moderne Varianten der Mannich-Reaktion, die die Bandbreite der klassischen intermolekularen Reaktion deutlich erweitern und eine effektive Kontrolle der Regio- und Stereoselektivitat ermoglichen, sind daher Gegenstand intensiver Forschung. Intramolekulare Reaktionen, insbesondere als Teil von Dominoreaktionssequenzen, fuhren haufig verbluffend einfach und elegant zu komplexen Zielverbindungen.

Moderne Varianten der Mannich‐Reaktion

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 methylene compound. These components condense with concomitant release of water to produce a new base, known as a ‘Mannich base’, in which the active hydrogen is replaced by an aminomethyl group (equation 1). A typical example is the reaction of acetophenone (1), paraformaldehyde (2) and piperidine (3) to produce phenyl β-piperidinoethyl ketone (4; equation 2). The formation of both a carbon-carbon and a carbon-nitrogen bond in this aminomethylation process makes the Mannich reaction an extremely useful synthetic transformation. In addition, Mannich bases have important synthetic applications as intermediates for other compounds. They also occur in natural products such as the alkaloids lycopodine (5), cocaine (6) and elaeocarpine (7)

The Bimolecular Aliphatic Mannich and Related Reactions

Synthesis of the new mannosidase inhibitors, diversity-oriented 5-substituted swainsonine analogues, via stereoselective Mannich reaction.

A direct synthesis of α-methylene ketones

Synthese regioselective de bases de mannich de cetones dissymetriques

Isomeric Mannich bases derived from unsymmetrical ketones can be synthesised regioselectively simply by selecting the reaction conditions; reaction of dimethyl(methylene)ammonium trifluoroacetate in trifluoroacetic acid yields the more substituted aminoketone while reaction of di-isopropyl(methylene)ammonium perchlorate in acetonitrile leads to the less substituted aminoketone.

Regioselective synthesis of Mannich bases from unsymmetrical ketones and immonium salts

Regioselective mannich condensation with dimethyl(methylene)ammonium trifluoroacetate: 1-(dimethylamino)-4-methyl-3-pentanone



intermediate: bis(dimethylamino)methane




product: 1-(dimethylamino)-4-methyl-3-pentanone





Keywords:

enamine or imine formation;
rearrangements;
trifluoroacetic acid

Yves Jasor

Papers

Synthese regioselective de bases de mannich de cetones dissymetriques

Regioselective synthesis of Mannich bases from unsymmetrical ketones and immonium salts

Regioselective Mannich Condensation with Dimethyl(Methylene)Ammonium Trifluoroacetate: 1‐(Dimethylamino)‐4‐Methyl‐3‐Pentanone

Regioselective synthesis of mannich bases from unsymmetrical ketones and immonium salts

Regioselective synthesis of mannich bases from disymmetric ketones