Mannich amino ketone formation

Both the above mechanisms are proposed in the literature with Mannich bases of nitroalkanes the substitution is clearly favored by the steric hindrance of the amine moiety, thus suggesting path 1, - whereas NMR studies on the reaction of P-amino-ketones with hydroxy coumarins do not reveal the presence of vinyl ketone intermediates. lodomethylated phenolic Mannich bases arc also claimed to react according to path 2, although the formation as by-products of dimers and methylene-bis-derivatives accounts for the participation of methylenequinone intermediates in the process. "... 

Tethering the alkene to the carbon atom of the nitrone allows the preparation of cw-l,2-disubstituted cycloalkanes such as 212. Examples in which the alkene is tethered to the nitrogen atom of the nitrone are also common. Thus, addition of formaldehyde to the hydroxylamine 213 promoted formation of the intermediate nitrone and hence the cycloadduct 214 (3.140). " Subsequent transformations led to the alkaloid luciduline. This synthesis illustrates a useful feature of the 1,3-dipolar cycloaddition reaction of nitrones, in that it provides an alternative to the Mannich reaction as a route to (3-amino-ketones, via reductive cleavage of the N-0 bond in the isoxazolidine and oxidation of the 1,3-amino-alcohol product. In another example of such an intramolecular cycloaddition reaction, the bridged bicyclic product 217, used in a synthesis of indolizidine 209B, was formed by addition of an aldehyde to the hydroxylamine 215, followed by heating the intermediate nitrone 216 (3.141).142... 

Ultimately, a complete retrosynthesis of a P-amino ketone leads to the three components needed in a Mannich reaction a ketone, an aldehyde, and an amine. The retrosynthesis of a P-amino ketone begins with making a disconnection between the alpha carbon and the carbon bearing the amino group (the beta carbon). This aldol-like disconnection leads to a nucleophilic alpha carbon (enol) and an electrophilic imine carbon (C=N). Further disconnection of the imine affords the two necessary building blocks for its formation an aldehyde and an amine. 

In the approaches toward a direct asymmetric Mannich reaction by enolate formation with the metal of the catalyst also, the well-proved systems of the analogous aldol reactions were widely applied. Here, it is referred to some of these protocols wherein a metal enolate is involved, as least as assumed and plausible intermediate [183]. Shibasaki and coworkers used a dinuclear zinc complex derived from linked BINOL ligand 371 for catalyst in direct Mannich reactions of a-hydroxy ketones 370 with Af-diphenylphosphinoyl imines 369 to give ti-configured a-hydroxy-P-amino ketones 372 in high yield, diastereoselectivity, and enantioselectivity (Scheme 5.97) [184]. The authors postulate the metal to form a chelated zinc enolate by double deprotonation of the a-hydroxy ketone. This enolate approaches with its Si-face to the Si-face of the imine, as illustrated by the transition state model 373, in agreement with the observed stereochemical outcome. It is remarkable that opposite simple diastereoselectivity arises from the Mannich reaction (anti-selective) and the previously reported syn-selective aldol reaction [185], although the zinc enolates... 

One of the important C-C bond forming reactions, for the formation of P-amino-ketones and -aldehydes, involves the Mannich-type reaction between preformed imines and silyl enol ethers. 

The first observation of what is today recognized as a Mannich reaction was made by Tollens in 1903 [107j. This important transformation was subsequently studied in great detail by Mannich, who recognized its significance and developed it into a general synthetic method in the early twentieth century [108]. Subsequent developments have made this reaction a powerful and widely applicable transformation for the stereoselective formation of /3-amino ketones [20, 34, 40-42, 106, 109, 110]. 

Benzene formed from photolysis of the 1 1 complex is a cage-escape product from 3(Jul-CHO+ /Ph ). Benzene formed from the photolysis of the 2 1 complex is an in-cage product from 3((Jul-CHO)2 /Ph ). The formation of 2 1 complexes of amino-substituted ketones and iodonium salts has been suggested to account for the high photosensitivity of polymeric Mannich bases with iodonium salts [102]. Formation of 2 1 donor iodonium cation complexes has been rationalized by consideration of the crystal structures of diphenyliodonium halides, which crystallize as dimers with square planar iodine atoms with two bridging halide counterions [102,108]. 

The chemoselective enolate formation from hydroxyketone (245) and isomerizable aliphatic Ai-Dpp imines (246) has been described. The Et2Zn/linked-BINOL complex (247) effectively promoted the Mannich-type reaction, affording P-alkyl-P-amino-a-hydroxy ketones (248) in high enantioselectivity and good yield (Scheme 100). ... 

The Mannich reaction is an excellent method for the synthesis of P-amino carbonyl compounds and their derivatives, and unmodified primary amino acids were found to be enormously useful for this important reaction. Cdrdova et al. [42] reported the first primary amino acid-promoted three-component Mannich reaction of ketone, p-anisidine, and aldehydes primary amino acids, such as L-alanine and L-vahne, were excellent catalysts and led to the formation of Mannich products with up to >99% ee. Barbas and coworkers [31] also showed L-tryptophan catalyzed the direct threeMannich reaction of hydroxyacetone, p-anisidine, and aromatic aldehydes good yields, high diastereoselectivity, and excellent ee were attainable. 

Following immediately the initial efforts on primary amino acids catalyzed aldol reactions, the application of primary amine acid in Mannich reaction has also been attempted. Cordova reported that simple primary amino acids and their derivatives could catalyze the asymmetric Mannich reactions of ketones with comparable results to those obtained in the catalysis of proline[28]. Later, Barbas [29] and Lu [30] independently reported that L-Trp or 0-protected L-Thr could catalyze anti-selective asymmetric Mannich reactions of a-hydroxyacetones with eiflier preformed or in-situ generated imines. The preference of anii-diastereoselectivity was ascribed to the formation of a Z-enamine, with the assistance of an intramolecular H-bond (Scheme 5.15). 

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