Michael additions of aliphatic aldehydes

Recently, there has been considerable progress in the synthesis of nitrogen-containing heterocycles based on (ox)indole skeleton. Oxindole derivatives serve as useful reaction partners in various domino transformations. Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral intermediates, which were further combined with diverse activated olefins or imines to afford spirocyclic oxindoles with high molecular complexity (Scheme 8.27). Spiro-oxindole derivatives were also assembled by a Michael/Michael/aldol cascade of oxindole and two equivalents of enal. " ... 

In 2006 Palomo and coworkers tested several prolinamides in the asymmetric Michael addition of aliphatic aldehydes to nitroalkenes. Hydroxy-proline-derived amides 13 were found to be the most active catalysts for this transformation, establishing the importance of the hydrojy group not only for reaction stereocontrol, but also for catalyst activity. However, 3-hydro>y-prolinamide 13b gave less satisfactory results in terms of stereocontrol, compared to the 4-hydro>y-prolinamide analogue 13a (Scheme 11.11). 

Scheme 11.36 Michael addition of aliphatic aldehydes to aromatic nitroalkenes using pyrrolidine (S)-35e HBr.

In 2013 Cozzi et al. prepared the 2-(diethylferrocenyl) pyrrolidine (S)-36 starting from ferrocenyl ethyl ketone (Scheme 11.37) and proved its effectiveness in different organocatalytic transformations, namely the Michael addition of aliphatic aldehydes to aromatic nitroalkenes (Scheme 11.38A) and the SNl-asymmetric a-allgflation of carhonyl compounds (Scheme 11.38B). ... 

The constrained tricyclic chiral secondary amine 43 was proposed hy Loh et al. in 2011 for the highly enantioselective organocatalytic Michael addition of aliphatic aldehydes to vinyl sulfones (Scheme 11.44). DFT calculations revealed that only 42-derived sy -enamine is formed due to steric congestions and that the naphthyl ring is puckered in the chiral pocket of the tricyclic system, efficiently shielding only one of the diastereotopic faces of the reactive enamine. ... 

In 2014, the group of Rahman reported the asymmetric Michael addition of aliphatic aldehydes and ketones to substituted tra s-(3-nitrostyrenes catalysed by aldo-ketoreductase mimicking peptides. A selected series of peptides, analogous to amino acid sequences of the enzyme, showed in all cases fair to excellent yields and diastereoselectivities with enantiomeric excesses of up to 71%. 

Optically pure 2-alkyl-3-(l//-indol-3-yl)-4-nitrobutanals (102) have been prepared in yield/de/ee up to 98/98/99% by Michael addition of aliphatic aldehydes, R -CHjCHO, to tran -indolylnitroalkenes, using (5)-diphenylprolinol TMS ether as organocatalyst. The products (102) are useful precursors to biologically active tryptamines. 

A combined system of PhjP and a cinchonidine-derived primary amine has been identified as an ideal catalyst for the Michael addition of aliphatic aldehydes to iV-aryl maleimides (with <99% ee). Mechanistic investigation, involving UV-vis, fluoreseenee emission (FL), NMR, circular dichroism (CD), and ESI-MS, revealed the existenee of the molecular assembly of phosphine and amine (248) with an arene-arene staeking, which is believed to play the key role ... 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

In the early 1970s Stetter and co-workers succeeded in transferring the concept of the thiazolium catalyzed nucleophilic acylation to the substrate class of Michael acceptors (Stetter 1976 Stetter and Schreck-enberg 1973). Since then, the catalytic 1,4-addition of aldehydes 6 to an acceptor bearing an activated double bond 131 carries his name. The Stetter reaction enables a new catalytic pathway for the synthesis of 1,4-bifunctional molecules 132, such as 1,4-diketones, 4-ketoesters and 4-ketonitriles (Stetter and Kuhlmann 1991 for a short review, see Christmann 2005). The reaction can be catalyzed by a broad range of thiazolium salts. Stetter and co-workers found the benzyl-substituted thiazolium salt 86a to give the best results for the addition of aliphatic aldehydes, whereas 86b and 86c were chosen for the addition of aromatic aldehydes. Any one of these three was found to be suitable for additions with heterocyclic aldehydes. Salt 86d was utilized with a, )-unsaturated esters (Fig. 15). 

Michael addition of aromatic or heterocyclic aldehydes (via cyanohydrins) to a,p-unsaturated systems. Also addition of aliphatic aldehydes catalyzed by thiazolium ylids... 

As a continuation of previously reported studies on enantioselective Michael additions of aldehydes to nitro-olefins, in 2012, Wennemers and coworkers investigated the asymmetric Michael addition between aliphatic aldehydes and more sterically hindered a,p-disubstituted nitro-olefins, mediated by L-proline-based tripeptides 18 and 19 (Scheme 13.14a). 

Scheme 6.103 Representative products provided from the 100-catalyzed asymmetric Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes.

Scheme 6.104 Key intermediates of the proposed catalytic cycle for the 100-catalyzed Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes Formation of imine (A) and F-enamine (B), double hydrogen-bonding activation of the nitroalkene and nucleophilic enamine attack (C), zwitterionic structure (D), product-forming proton transfer, and hydrolysis.

Evidently, although the system tolerates both aromatic and aliphatic aldehydes, the introduction of an electron-withdrawing substituent on the aromatic substrate results in a decreased yield. To gain information about the mechanism of the overall tandem reaction, kinetic studies were carried out to identify the rate-determining step. Changing the catalyst concentration in the reaction between 3-methylbutyraldehyde, nitromethane and dimethyl malonate revealed that the reaction is first order in nickel catalyst, indicating that the Michael addition of dimethyl malonate to the nitroalkene is the ratedetermining step. 

Early work by Tomioka and coworkers [39] described a two-component Michael/ aldol process to cyclopentenes. Furthermore, rhodium-assisted Michael/aldol processes to cyclopentanes and cyclohexanes have also been reported [40]. Later, a Michael addition reaction in combination with an adehyde a-alkylation reaction was reported for the highly stereoselective formation of y-nitroaldehydes 50 [41]. In this publication, a series of aliphatic aldehydes 49 (at Rj) and ( )-5-iodo-l-nitropent-1-ene 48 were reacted in the presence of the organocatalyst 1 and benzoic acid in dimethyl sulfoxide (DMSO) to afford the resulting cyclopentene ring system 50 (Scheme 7.9). The diastereo- and enantioselective process follows the proposed mechanism beginning with enamine activation of the aldehyde to 51 by the catalyst 1 (blocking the re face), and Michael addition of 48 occurs at its more accessible si face. The full enamine-enamine mechanism, illustrated in Scheme 7.9, provided... 

The first enantioselective, organocatalytic approach for the synthesis of a-methylene-8-lactone (194) and 8-lactam (195), utilizing the Michael addition of the aliphatic aldehyde (193) to ethyl 2-(diethoxypho-sphoryl)acrylate (192), in the presence of the pirolidyne derivative (196) has been presented by Jorgensen and co-workers (Scheme 68). ... 

The application of this procedure to the condensation of a-nitroalkanones with a-alkyl-q ,j8-imsaturated aldehydes afforded, in a one-pot synthesis, functionalized, bridged, and bicyclic lactones containing 10-, 11-, 13-, and 15-membered rings. Recently, Ballini et al. showed that the Michael addition of primary aliphatic nitro compounds to a,p -unsaturated enones performed in aqueous media provided the one-pot synthesis of 1,4-diketones, 1,4-diols, S-nitroalkanols, or hydroxytetrahydrofurans by appropriate choice of reaction conditions. ... 

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