Cascade Michael alkylation

Historically the first cascade Michael-alkylation reaction was described almost simultaneously by the Wang and the Cordova groups by using a,(i-unsaturated aldehydes with bromomalonates or bromoacetoacetates. The reaction afforded cyclopropanes or cyclopentenones depending on the position of the halogen and was catalyzed by diphenylproHnol TMS ether (6) (Scheme 25.2) [5a,b]. 

Scheme 25.2 Enantioselective cascade Michael-alkylation reactions and the postulated mechanism.

The cyclopropanation of activated olefins by cascade Michael/a-alkylation reaction using a-halomalonates or bromonitromethane as functionalized pronucleophiles has also been faced with the application of H-bonding catalysis. 

Scheme 7.67 Two examples of cascade Michael/a-alkylation for the synthesis of cyclopropanes.

Scheme 7.79 Asymmetric cyclopropanation of 2-bromocyclopentenone by cascade Michael/a-alkylation.

Pesciaioli, R, Righi, R, Mazzanti, A., Bartoh, G., Bencivenni, G. (2011). Organocatalytic Michael-alkylation cascade the enantioselective nitrocyclopropanation of oxindoles. Chemistry - A Enropean Journal, 17, 2842-2845. 

Cyclopropanation of a,P-unsaturated aldehydes with diethyl bromomalonate, proceeding via a cascade Michael/a-alkylation process, was carried out in the presence of catalyst 100 in water to give compounds 112 (Figure 24.34). This is a case of an on water organocatalytic reachon. Indeed, organic solvents such as CHCU or THF gave comparable levels of stereoselechvities but lower yields with respect to water [126],... 

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>. 

Scheme 7.32 Enantioselective cyclopropanation of enones by Michael/a-alkylation cascade reaction.

A-vinylindoles took place. Moreover, the gold-catalyzed cyclization of 2-alkynylanilines can be combined with a gold-catalyzed Michael addition to enones, which afforded 3-alkylated indoles with good yield. Gold-catalyzed hydroamination/hydroarylation cascades of polyenyne-substituted anilines leading to condensed aromatics have been described recently. ... 

A BINAP-derived bifunctional thiophosphoramide gives >98% del>99% ee in Michael addition of cyclohexanones to both aryl- and alkyl-substituted nitroolefins. Imidazolylmethyl ketones undergo one-pot Michael-aldol cascade reactions with Q ,/3-unsaturated aldehydes in DCM at 20 °C using the simple organocatalyst, prolinol... 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

Wang elegantly demonstrated the potentiality of chiral diarylprolinol ether 54 in the synthesis of chromanes 56 via enantioselective Michael-type Friedel-Crafts alkylation/cychzation cascade synthetic sequence between 5a and a,p-unsaturated aldehydes 37a [30a]. Under optimal conditions, moderate diastereoselectivity and high enantioselectivity were obtained. Differently, phenol was found unreactive (Scheme 5.17a). The same team years later documented also the activity of a rosin-derived tertiary amine-thiourea 55 in similar process involving 1- and 2-naphthols and P,y-unsaturated a-ketoesters 25 (Scheme 5.17b) [30b]. A proposed model of the enantiodiscrimi-nating step of the reaction is also provided by the authors (58). 

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]. 

D. B. Ramachary, M. Kishor, Org. Biomol. Chem. 2010, 8, 2859-2867. Direct catalytic asymmetric synthesis of highly functionalized tetronic acids/tetrahydro-isobenzofuran-1, 5-diones via combination of cascade three-component reductive alkylations and Michael-aldol reactions. 

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