Quadruple cascade reactions

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). 

Double, triple, and even quadruple Heck-Diels-Alder cascade reactions involving 1,4-diiodo-, 1,3,5-triiodo-, or 1,2,4,5-tetraiodobenzene, respectively, andbicyclo-propylidene (16) have been accomplished (cf. Scheme 8.5) [121b]. The efficiency of these sequences, in which each carbopalladation across the highly strained alkene is followed by a cyclopropylmethyl to homoallyl rearrangement with concomitant 3-hydride elimination to yield an allylidenecyclopropane, which subsequently undergoes a smooth [4 + 2] cycloaddition (Scheme 8.5), is quite remarkable [121bj. 

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]. 

SCHEME 2.53 Synthesis of tetrahydro-6//-benzo[c]chromenes 168 via quadruple cascade reaction. 

Because of these numerous reports, only selected examples are provided in this section. Most of them deal with double cascade reactions, mainly centered on Michael-type reactions. However, a few remarkable reports involving triple and quadruple cascade reactions are also presented. 

Quadruple Cascade Reactions Based on previous achievements, quadruple cascade reactions have also been developed. Most of them are centered on the Michael reaction in association with an aldol condensation. 

An organocatalytic microwave-assisted quadruple cascade reaction of P-nitrostyrenes with an excess of acetaldehyde in the presence of (S)-diphenyl-prolinol TMS-ether was described by Enders [42] and coworkers (Scheme 21.18). 

Scheme 21,18 Organocatalytic quadruple cascade reactions of acetaldehyde and P-nitrostyrene.

Scheme 42.18 Quadruple cascade reaction by way of an iminium ion-enamine-iminium ion-enamine activation of aldehydes. Protocol point all substrates added at the outset of the reaction.

Scheme 42.19 Enders quadruple cascade reaction. Protocol point acrolein (69) added slowly over 12h (syringe pump addition).

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]. 

In 2010, Enders and co-workers developed a quadruple cascade AFC/ Michael/Michael/aldol condensation reaction of indoles, acrolein, and nitroalkenes under the catalysis of diphenylprolinol TMS-ether catalyst (S)-104 following an iminium/enamine/iminium/enamine activation sequence (Scheme 6.42). " The reaction provided a straightforward and efficient entry to 3-(cyclohexenylmethyl)-indoles 105 bearing three stereogenic centers in moderate to excellent yields (23-82%) and excellent stereoselectivity (91 9->95 5 dr and 94->99% ee). 

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). 

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]. 

P. Kotame, B.-C. Hong, J.-H. Liao, Tetrahedron Lett. 2009, 50, 704—707. Enantioselective synthesis of the tetrahydro-6//-benzo[c]chromenes via domino Michael-aldol condensation control of five stereocenters in a quadruple-cascade organocatalytic multi-component reaction. 

The use of phosphoric acid ml-lGd for the catalysis of a tandem double F-C reaction gave rise to fluorene derivatives (up to 96% ee) by the reaction between indoles and 2-formylbiphenyl derivatives [74]. Vinyl indole derivatives combined with a,P-unsaturated aldehydes gave rise to functionalized tetrahydrocarbazoles with two or more stereocenters via an intermolecular triple cascade process by means of secondary amine 7a catalysis [75]. Catalyst 7a also promoted a quadruple F-C/Michael/Michael/aldol condensation reaction between indoles, acrolein, and aromatic nitroolefins (Scheme 35.19) [76]. This work provides a straightforward... 

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]. 

Reversing the position of the aldol electrophile, Enders and coworkers developed a type ce approach to complex 3-pyrrolin-2-ones that involved a quadruple cascade process (Scheme 91 2014S1539). Treatment of cinnamaldehyde (353) and the a-ketoamide 354 with pyrrolidine catalyst 355 and NaOAc gives the fused 3-pyrrolin-2-one 357. The mechanism of the reaction includes a Michael addition by the amide followed by aldol condensation to generate the 3-pyrrolin-2-one intermediate 356 subsequent Michael and aldol transformations with a second equivalent of 353 then gives the fused cyclopentene ring. 

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