Imines double Mannich reaction

Piperidones (19) have been prepared from ketones (MeCOCH2R) and aromatic imines (Ar -N=CHAr ) via a double Mannich reaction and tandem cyclization. The l2-induced room temperature reaction is highly stereoselective, giving only one of four possible isomers. Chelation and hydrogen-bonding effects have been invoked to explain the specificity(g)... 

In 2009, List and coworkers reported a highly diastereo and enantioselective proline-catalyzed double Mannich reaction of acetaldehyde with A-Boc imines [3], The treatment of 1 equiv of acetaldehyde with 3 equiv of A-Boc imine derived from benzaldehyde in the presence of 20 mol% of L-Pro produced the double Mannich adduct 2 in quantitative yield and with exceptionally high diastereo and enantiose-lectivities (dr > 99 1, ee > 99%) (Scheme 12.2). The reaction was performed with a variety of A-Boc imines, namely aromatic and heteroaromatic substituted imines, and furnished the products in excellent yields (76-99%) and with similar stereoselectivities (dr > 99 1, ee > 99%). Even the unstable isovaleraldehyde-derived A-Boc imine gave the double Mannich adduct stereoselectively, albeit with a moderate yield (30%). 

The one-pot cross double Mannich reactions with two different imines led to the formation of a complex mixture containing Mannich adducts, homocoupling products, as well as the desired cross-Mannich product. In order to circumvent this synthetic problem, the desired cross-Mannich targets were prepared by isolating the initial mono-addition products, which were then engaged in a second L-Pro-catalyzed Mannich reaction with a different N-Boc imine. Under these conditions, the cross-Mannich compounds were obtained in reasonably good yields and high selectivities. 

Chandler, C., Galzerano, R, Machrowska, A., List, B. (2009). The proline-catalyzed double Mannich reaction of acetaldehyde with AI-Boc imines. Angewandte Chemie International Edition, 48, 1978-1980. 

Scheme 28.8 Double Mannich reaction of acetaldehyde with imine.

Moreover, enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 1.11). The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-Cj-symmetric p,p -diaminoaldehydes 37 with extremely high stereoselectivities (>99 1 dr, >99% ee) [13], A similar approach with ketones was also realized [14],... 

Three-component Mannich reactions of cyclohexanone and anilines with aromatic aldehydes, in the presence of HjO, have been promoted by amphiphilic isosteviol-proline organocatalysts with excellent de and eef DFT calculations indicate that the proline-catalysed single and double Mannich reactions between acetaldehyde and A-Boc imines, to give (5) and (5,5)-conformation products, respectively, are stereochemically controlled by hydrogen bonding." High enantioselectivity has been reported for L-proline-catalysed addition of aldehydes to 2-aryl-3//-indol-3-ones," ... 

Keywords Catalyst, Alkylation, Allylation, Arylation, Mannich reaction, Carbon-nitrogen double bond, Imine, Nitrone, Aldimine, Organozinc reagents, Silyl ketene acetal, Silyl enol ether, Amine, (3-Amino acid... 

Catalytic enantioselective Mannich reactions - addition reactions of enolates to the imine double bond - were less developed than the corresponding aldol protocols. In view of the analogy between the carbonyl and the imine group, it is not very surprising that many catalysts that had proven their efficiency in aldol protocols were tried to be applied in the asymmetric Mannich reaction as well. However, there are some inherent features that make the Mannich reaction more difficult to... 

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... 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Ketimines and aldimines proved to be good substrates [73]. Based on the structure modification, nuclear magnetic resonance (NMR) study, kinetic study, and computational study, they proposed a double hydrogen bond structure between the acidic N-H protons and the imine lone pair to activate the electrophile toward the attack by the cyanide ion (Figure 2.15) [74]. The catalyst system is applicable to the Mannich-type reaction of N-Boc-aldimine with ketene silyl acetals to give corresponding P-amino esters in 86-98% ee (Scheme 2.25) [75]. Hydrophospho-nylation of aldimines with bis(2-nitrobenzyl)phosphite by means of (4d) furnished a-amino phosphonates in good enantioselectivity (Scheme 2.26) [76]. 

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