Mannich indirect

The less highly substituted Mannich bases can also be prepared directly from ketones and dimethyl(methylene)ammonium trifluoroacetate by the procedure reported here, which takes advantage of the isomerization of Mannich bases in trifluoroacetic acid. (In acetic acid the Mannich bases undergo elimination of dimethylamine to give a-methylene ketones.) This method is rapid and affords products having an isomeric purity of at least 90% without difficult separations. The 49-57% yield of l-(di-methylamino)-4-methyl-3-pentanone obtained with this procedure compares favorably with the overall yields of amino ketones prepared by the indirect routes mentioned previously. 

The Akiyama group tested various BINOL phosphates 3 as catalysts for the indirect Mannich reaction of aldimines 8 derived from 2-aminophenol with silyl ketene acetals 9 (Scheme 4). All of these Brpnsted acids furnished P-amino ester 10a in (nearly) quantitative yields. Both the reaction rates (4-46 h) and the enantioselectivities (27-87% ee) were strongly dependent on the nature of the substituents at the 3,3 -positions. 

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],... 

In recent years a number of methods have been developed for the preparation of dialkyl(methylene)ammonium salts (Mannich reagents), and their use in Mannich-type condensation reactions under anhydrous conditions has improved the scope and efficiency of this important synthetic process. However, the orientation of the Mannich reaction may nevertheless be difficult to control. Apart from the work of the submitters, the preparation of isomer-ically pure Mannich bases has only been achieved by indirect... 

Domino Reactions Initiated by the Indirect Mannich Reaction... 

The classic direct Mannich reaction discovered in 1912 [192a] is an aminoalkylation of carbonylic compounds involving ammonia (or a primary or secondary amine derivative), a non-enolizable aldehyde (usually formaldehyde) or a ketone, and an enolizable carbonyl compound, leading to P-aminocarbonyl derivatives [192b-e]. The indirect version of the Mannich reaction is the corresponding two-component reaction of a preformed iminium salt [193] and an enolizable carbonyl compound. 

In parallel, Akiyama used the same type of catalysts for highly enantioselective indirect Mannich-type reactions [8]. His group also disclosed that these chiral phosphoric acid derivatives can catalyse the aza-Diels-Alder reaction with high stereoselectivity [75]. In addition, chiral-phosphoric acids can mediate similar transformations as the proline-catalyzed domino Mannich/aza-Michael reactions with high enantioselectivity [76]. 

The Mannich reaction represents a useful extension of aldol-type approaches for the stereoselective formation of C-C bonds with concomitant introduction of O- and N-functionality. In this reaction two carbraiyl compounds and an amine react to form p-amino-carbonyl compounds. Besides indirect variants using preformed enolates the use of unmodified nucleophiles (direct variant) has attracted considerable interest (92). Therefore, it is not surprising that the first example of a direct organocatalytic Mannich reaction was published only shortly (93) after the first proline-catalyzed aldol reaction (28). p-Anisidine (102) is commonly used for... 

In 2008, Barbas et al. reported the first primary amine-containing amino acid-catalysed indirect a n -Mannich reactions of dihydroxyacetone and acyclic protected dihydroxyacetone derivatives with a variety of imines derived from both aliphatic and aromatic aldehydes.In spite of moderate diastereoselec-tivities, good to high yields and enantioselectivities were obtained by using an L-threonine derivative as the organocatalyst in A -methylpyrrolidinone as the solvent and 5-methyl-l-7/-tetrazole as an additive, as shown in Scheme 3.14. 

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