Michael-initiated cascade reaction

In 2012, a comparable combination of catalysts was employed by Jorgensen et al. to induce a Michael-initiated cascade reaction of atyloTgr-acetaldehydes to give the corresponding chiral 3,4-dihydrocoumarins. As shown in Scheme 2.33, these important products were produced in good yields and moderate to high enantioselectivities of up to 96% ee. 

With a similar strategy of combined diarylprolinol silyl ether and N-heterocyclic carbene catalysts, j0rgensen and coworkers [21] examined the cascade reaction of easily accessible i-keto heteroaryl-sulfones as nucleophiles with a,P-unsaturated aldehydes (Scheme 43.11). In this cascade reaction, following the initial iminium ion-catalyzed Michael reaction of nucleophiles to a,(i-unsaturated aldehydes, the subsequent step was then promoted by carbene catalyst 57 to afford 2,4-disubstituted cyclopentenones 55 via an intramolecular benzoin condensation initiated Smiles rearrangement. The superiority of combinational use of two catalysts in the similar Michael/benzoin cascade reaction was also independently demonstrated by Enders et al. (Scheme 43.12) [22]. 

In addition to imininm-initiated cascade reactions, two of the steps in enamine-activated cascade reactions can also be enforced by cycle-specific catalysis. It is well known that diphenylprolinol silyl ether catalyst 34 is optimal for diverse enamine-mediated transformations to fnmish prodncts with high enantioselectivities. However, similar to imidazolidinone catalysts, it proved to be less effective or ineffective for bifunctional enamine catalysis. Cycle-specific catalysis via an aza-Michael/Mannich sequence by combining 34 and either enantiomer of proline was thus developed to generate 206 in about 60% yields with excellent diastereo- and enantioselectivities (Scheme 1.89) [139]. 

Abstract Cascade reactions involving a transition metal-promoted step and a Michael-type addition process have emerged as a powerful tool to construct cyclic and polycyclic structures. In this review, recent advances in this field are presented. The first part is related to cycloaddition reactions based on zwitterionic jr-allylPd complexes. The second part deals with Michael initiated metal-catalyzed cyclofunctionalization reactions of unactivated C C jt-bonds. Parts three and four feature reactions where an initial Michael addition reaction is followed by either a coupling reaction or an electrophilic trapping. Part five is devoted to Michael terminated reactions. 

Another type of metal-catalyzed cascade reaction using a Michael addition step was the use of this latter in the terminating step of the reaction in order to trap an initial intermediate created by a metal-catalyzed step. This particularly useful strategy was developed by several groups allowing the creation of polyfunctionalized structures. 

Increasing importance has to be attributed to modem tandem (or cascade ) techniques—reaction sequences that can be performed as a one-pot procedure because the first reaction step creates the arrangement of functional groups needed for the second to occur. Schemes 5-7 present some in situ preparations for iminium species, which can then react further with appropriate nucleophiles that are already present (preferably in the same molecule). Most elegantly, in situ generation of iminium ions for tandem processes was performed by a 3,3-sigmatropic (aza-Cope-type) rearrangement (Scheme 5), but also by initial Michael-type addition reactions to vinyl-substituted Atio... 

It was suggested that this reaction proceeds via the DKR-mediated Michael-retro-Michael-Michael-Michael cascade reaction pathway the initially formed Michael adduct undergoes a DKR process in the presence of catalyst 81b, where the deprotonation of the highly acidic proton of 109 by the quinuclidine base of the catalyst leads to a reversible and stereoselective retro-Michael-Michael-Michael process. This proposal was supported by the observation that the reaction of racemic 109 with nitrostyrene under identical conditions depicted in Scheme 9.36... 

Conversely, when the reaction was carried out by using Amberlyst A15 (200%) in the presence or absence of liquid BEMP (10%), the only observed reaction product was substituted pyrrole 135, which was isolated in 68% yield product 134 was not present at all in the reaction mixture. However, when the reaction was repeated by using a combination of PS-BEMP (10%) and Amberlyst A15 (200%), the sole reaction product was the desired tetracyclic product 136 -obtained in 83% yield as a 1 1 mixture of diastereoisomers. By using sub-stoichiometric quantities of PS-BEMP (10%) and Amberlyst A15 (50%), an 85% conversion into 136 after 5 days was produced. These results demonstrate that PS-BEMP and Amberlyst A15 can operate as mutually compatible strongly basic and strongly acidic reagents, respectively, in the same vessel to facilitate the Michael-initiated N-acyl iminium ion cyclization cascade. 

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

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 similar cascade reaction was reported by Melchiorre and co-workers [69] in 2008. Initially, this triple cascade reaction between an enolizable aldehyde, 2-cyanoacrylate, and enal consists of the aldehyde addition to a 2-cyanoacrylate derivative (108), promoted by a diphenylprolinol derivative (VII). Next, the resulting adduct reacts with enal via a Michael addition promoted by the same catalyst. Finally, an intramolecular aldol reaction takes place between the formed enamine and the aldehyde, leading to the cyclohexane 109. It should be noticed that the use of an acid as a co-catalyst is cmcial to obtain high levels of stereoselectivity. 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

Enders et al. [75] developed a synthesis of polyfunctionalized 3-(cyclohex-enylmethyl)-indoles 125 via a quadruple domino Friedel-Crafts-type Michael-Michael-aldol condensation reaction, in 2010. This cascade sequence is initiated by a Friedel-Crafts reaction of indole (126) by an iminium activation mode to the enal, followed sequentially by an enamine- and an iminium-mediated Michael addition. After an intramolecular aldol-condensation, four C-C bonds are formed and the domino product is constructed bearing three contiguous stereogenic centers (Scheme 10.34). 

Remaining in the field of hetero-Michael reaction, Gong et al. disclosed a four-component quadruple cascade reaction activation initiated by oxa-Michael addition of alcohol to acroleins providing an easy and direct access to highly functionalized chiral trisubstituted cyclohexene derivatives 170 (Scheme 2.54) [81]. 

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. 

In an effort to develop new cascade reactions, Zhang et al. envisioned that a linear aldehyde can also be genaated in situ via an extra iminium catalysis from an ot,p-unsaturated aldehyde prior to the triple cascade reaction. Therefore, there would be a possibility of extending the triple cascade reactions to four-component cascade reactions. Based on this design, a four-component quadruple cascade reaction through iminium-enamine-iminium-enamine sequential activation initiated by oxa-Michael addition of alcohol to acrolein in moderate yield (about 50%), excellent diastereoselectivities (>20 1), and excellent enantioselectivities (>99% ee) was accomplished (Scheme 1.33) [47]. 

A similar organocatalytic quadruple domino Friedel-Crafts/Michael/Michael/ aldol condensation reaction initiated by Friedel-Crafts reaction of indole to acrolein was also developed by Enders et al. [48], as well as a microwave-assisted qnadruple cascade organocatalytic Michael/Henry condensation/Michael/aldol condensation anploying acetaldehyde and nitroalkenes as substrates [49]. 

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