Michael addition nucleophilic cascade reaction

In a continuation of enantioseleclive cascade sulfa-, oxa-, and aza-Michael/aldol/ dehydration cascade reactions, Wang et al. envisioned that the employment of a nucleophilic carbon atom for the initial Michael addition could enable the generation of two new C—C bonds in sequential [3+2] reactions. 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

The mechanism of these MCRs involving Meldrum s acid should include Knoevenagel condensation and Michael addition cascade process [100, 113] (Scheme 37). To form positional isomeric reaction product, arylliden derivatives of Meldrum s acid are attacked by exocyclic NH2-group instead of endocyclic nucleophilic center. 

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

Alternatively, a cascade Michael/aldol process has also been devised for the preparation of cyclopentenes also using this iminium/enamine manifold. In this reaction, a malonate reagent containing a functionalized side chain incorporating a formyl group at the appropriate position has been used as the nucleophile initiating the cascade process (Scheme 7.20). The reaction started with the Michael addition of the malonate to the a,(3-unsaturated aldehyde... 

Synthesis of chiral heterocycles by domino organocatalytic processes has also been intensively studied. In particular, various benzo-fused heterocycles, such as chiral chromans, " thiochromanes, hydro-quinolines, dihydropyranes, or thiopyranes were investigated. These organocatalytic sequence were typically initiated by a hetero-Michael addition of a sulfur, oiqrgen or nitrogen nucleophile, which triggers the formation of an enolate/enamine that adds to the ortho electrophile terminating the cascade reaction. An elimination step or an additional cyclisation step follows (Scheme 8.25). 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

Alkylideneindolones are particularly good electrophiles, especially toward Michael additions, and therefore constitute excellent starting materials for the synthesis of spirooxindoles by multiple bond-forming approaches. The general strategy of the cascade reactions consists of an initial Michael reaction followed by a nucleophilic addition of the in situ formed enolate intermediate to various electrophiles. In the last years, several electrophilic partners with different scaffolds that lead to formal cyclizations, such as [3+2] cycloadditions [8a], Diels-Alder reactions [8b], and cyclopropanation [8c], have been used to afford a plethora of new spirooxindole scaffolds with excellent stereocontrol. 

Two C-C Bond-Forming Events In 2008, Frechet and coworkers described an impressive asymmetric cascade reaction promoted by soluble star polymers with core-confined catalytic entities [10]. The encapsulation of catalysts into soluble star polymers allowed the use of incompatible catalysts and prevented undesired interactions between these catalytic systems. The organocascade corresponded to a nucleophilic addition of Af-methylindole to a,p-unsaturated aldehydes followed by a Michael addition of the adduct to methylvinylketone (MVK) in the presence of H-bonding additive (Scheme 12.5). Each catalyst - imidazolidinone 8 for the nucleophilic addition and diphenylprolinol methyl ether 9 for the Michael addition - or their combination cannot mediate both reaction steps. In particular, p-toluenesulfonic acid (p-TSA) diminished the ability of the chiral pyrrolidine 9 to effect enamine activation. Therefore, p-TSA and 9 were encapsulated in the core of star polymers, which cannot penetrate each other. Imidazolidone 8 was added to the acid star polymer and diffused to the core to form the salt, which allowed the iminium activation and catalyzed the first step. The second step was catalyzed by the pyrrolidine star polymer in presence of the H-bonding additive 10, which... 

The synthesis is initiated by the organocatalyzed cascade that activates a,p-unsaturated aldehyde 8 with the formation of an iminium ion (Scheme 14.2). In this way, the imidazolidinone catalyst allows hydride transfer from the Hantzsch dihydropyridine 9 onto the highly activated conjugated alkene 11, which creates the nucleophilic enamine intermediate 12. Because of the chirality of the organocatalyst, stereoselective Michael addition (97% ee) to the adjacent enone occurs, with minor preference for the cis diastereomer (2 1 dr). Fortunately, this undesired diastereomer slowly epimerizes to the required trans isomer, which produces (-l-)-ricciocarpin A when treated with samarium triisopropoxide. Besides the Cannizzaro-like redox disproportionation, which allows the lactone producing Evans-Tihchenko reaction to occur, samarium(III) also enhances the epimerization to the trans isomer and therefore produces the desired isomer in high selectivity. 

Organocatalysis have emerged recently as one of the cornerstones for the enanti-oselective synthesis of C-C or C-heteroatom bonds. Owing to the easy prediction of the stereochemical outcome of the reactions, iminium activation and specific Michael reactions is one of the most studied reaction types in organocatalysis. In the literature, we can find multiple approaches to the organocatalytic Michael reaction using different catalysts or nucleophiles, most of them with exceptional levels of stereoselectivity. Moreover, these simple additions to enals or enones have inspired multiple organocatalytic tandem and cascade reactions and, in our view, open up a new pathway for the enantioselective construction of complex scaffolds in one-pot procedures. 

Jia et al. reported a novel Michael/aza-Henry reaction of well-designed chalcones 217 and nitromethane 218 catalyzed by thiourea 130c (Scheme 2.60). Initiated by the Michael addition of nitromethane to an electron-deficient double bond, the resulting intermediate subsequently underwent an aza-Henry reaction to furnish multisubsti-tuted tetrahydroquinolines 219a with up to 20 1 dr and >99% ee [86a], Later, the same group presented an alternative way to construct the same skeletons with different diastereoselectivities [86b], which employed nitrogen as the nucleophilic site to trigger the cascade process (Scheme 2.60). Very recently, a multifunctional... 

Recently, Lin et al. demonstrated that the propargyl alcohol could participate in such a transformation for the synthesis of chiral dihydrofurans [53]. The reaction began with a challenging oxa-Michael addition to cinnamaldehyde derivatives, which was followed by a secondary amine/Pd complex-catalyzed nucleophilic addition/ isomerization of the alkyne moiety in excellent yields and enantioseleclivities (Scheme 9.58). Since the oxa-Michael addition of propargyl alcohol to 0[,P-unsaturated aldehydes was a slow process, this cascade reaction proceeded through a dynamic kinetic asymmetric transformation (DYKAT) process, whereby it made the overall reaction proceed efficiently and with high stereocontrol using the second reaction with precise stereocontrol to shift the first reversible oxa-Michael addition selectively. 

A new cascade reaction of isocyanides, chromone 3-carboxylic acid (311), and nucleophiles (ROH, RNH2, and NaN3), catalysed by Sc(OTf)3 under microwave irradiation, has been developed as a multicomponent method for the preparation of chromone-2-carboxamides and chromone-2-carboxamido-3-esters (313). The sequence apparently commences by the Michael addition of RN=C to generate intermediate (312). ° ... 

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