Michael cascade

Novel aldol-type reactions under Cinchona-deriwed chiral thiourea catalysis was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol reaction was presented. The reaction involves a tandem reaction catalyzed via hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product with three stereogenic centers (Scheme 28). hi the reaction of 2-mercaptobenzaldehyde 128 and a,P-unsatnrated oxazolidinone 129, the desired benzothiopyran 130 was formed smoothly in high yield and excellent stereoselectivity. 

This dual enamine/iminium activation profile in cascade Michael/aldol reactions can also be found even in some early reports, mostly focused on the self-dimerization of enals catalyzed by proline or analogues derived thereof, which generally proceeded with low enantioselect vities. There is not a clear and definitive mechanistic pathway confirmed for these reactions, although the most widely accepted proposal for the dimerization of enals (Scheme 7.4) ° involved sequential activation of one molecule of the substrate as a dienamine (Michael donor) and another molecule as iminium ion (Michael acceptor). 

Following a similar reaction design, a cascade Michael/aldol reaction has been studied using other different 1,3-dicarbonyl compounds for the building up of highly functionalized cyclohexanes containing multiple stereogenic... 

Scheme 7.15 Synthesis of polysubstituted cyclohexanones by cascade Michael/aldol reaction of P-ketoesters with a,P-unsaturated ketones.

Scheme 7.16 Synthesis of cyclohexenones by cascade Michael/aldol/dehydration sequence.

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... 

Scheme 7.19 Cascade Michael/aldol reaction for bicyclo[3.2.1]octanes.

Scheme 7.20 Cascade Michael/aldol/dehydration reaction for the formation of cyclopentenes.

Scheme 7.23 Cascade Michael/intramolecular condensation for the synthesis of cyclohexenes.

Scheme 7.35 Cascade Michael/Wittig reaction for the synthesis of cyclohexenones.

On the other hand, there is a report regarding a cascade Michael reaction followed by intramolecular nitro-Mannich (aza-Henry) reaction occurring between imides derived from diethyl aminomalonate and nitrostyrenes using thiourea 68a as catalyst (Scheme 7.63). This reaction results in a formal [3 + 2] cycloaddition between these two reagents, with this aminomalonate-derived... 

Scheme 7.64 Cascade Michael/Michael reaction for the asymmetric synthesis of highly functionalized cyclopentanes.

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.

In a completely different context, a cascade Michael/intramolecular addition process involving nitroalkenes and isocyanoesters has been developed, which results in a formal [3 -I- 2] cycloaddition reaction and therefore consisting of a direct and very efficient methodology for the asymmetric synthesis of 2,3-dihydropyrroles (Scheme 7.70). ° The reaction was catalyzed by cinchona... 

Scheme 7.78 Enantioselective synthesis of 4-alkylidene glutamic acids by cascade Michael/elimination process.

There are a couple of examples of cascade processes starting by a Michael-type addition of a carbon nucleophile proceeding under phase-transfer eatalysis conditions which deserve to be mentioned at this point. The first one eonsists of an enantioselective cyclopropanation of 2-bromocyclopentenone by a cascade Michael/intramolecular nucleophilic displacement in which a variety of C-H acidic carbon pro-nucleophiles such as nitromethane, cyanomethylsulfone and benzyl cyanoacetate reacted with this Michael acceptor in the presence of a quinidinium salt of type 67 (Scheme 7.79). In addition, the conditions needed to be optimized for each Michael donor employed, requiring a different catalyst and inorganic base for each case. Under the best conditions, the final cyclopropanes were obtained in moderate yields and enantioselectivities, albeit as single diastereoisomers. 

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

Related cyclopropanations have also been reported using sulfonium and telluronium ylides as intermediates. In particular, the cyclopropanation of enones has been carried out employing an allyl bromide as the cyclopropa-nating reagent and sulfonium and telluronium salts 134 and 135 as pre-catalysts (Scheme 7.84). These species, in the presence of a base, generated the corresponding ylide which underwent the cascade Michael/intramolecular nucleophilic substitution and it is in this second step that the real catalytically active species is released, able to interact with another molecule of the allyl bromide and thus regenerating the sulfonium or telluronium salts pre-catalysts, which can afterwards continue in the catalytic cycle. The substitution at the... 

Scheme 2.118 Cascade Michael/Michael/Wittig reaction.

Bromo methallyl sulfone, prepared from methallyl phenyl sulfone, has proven to be a good substrate for stereoselective synthesis of trisubstituted methylenecyclopentanes with a variety of different Michael receptors. For example, the trans trans-trisubstituted methylenecyclopentane was efficiently prepared in 93% yield by a cascade Michael addition/cyclization beginning with ethyl ( )-crotonate (eq 22). The phosphonate sulfone reagent, readily available from methallyl phenyl sulfone, was used for the selective synthesis of 1,3-dienes. The synthesis included... 

Scheme 1.40 Silylated biphenylprolinol-catalysed triple cascade Michael addition-Michael addition aldol reactions.

Organocatalytic, enantioselective cascade Michael-aldol condensation catalyzed by readily available (5 )-diphenylprolinol triethylsilyl ether gives synthetically useful, highly functionalized chiral cyclopentenes (Scheme 6.12) [14],... 

Wang, J., Li, H., Xie, H., Zu, L., Shen, X., Wang, W. (2007). Organocatalytic enantioselective cascade Michael-aldol condensation reactions efficient assembly of densely function-aUzed chiral cyclopentenes. Angewandte Chemie International Edition, 46, 9050-9053. 

One of the first examples of this type of reactions was reported in 2009 by Melchiorre and coworkers with a three-component cascade Michael-Michael-aldol reaction with unsaturated aldehydes as electrophiles or a complementary consecutive Michael-Michael sequence with enones [9]. In the first case (Scheme 10.1),... 

In 2011, Hong and coworkers reported the synthesis of spirodihydrocoumarins in excellent yields and enantioselectivities [48]. The reaction involved a cascade Michael hemiacetal formation between 2-oxocyclohexanecarbaldehyde (79) and 2-hydroxy nitrostyrenes 80, followed by the oxidation of resulting intermediate. The cascade reaction was efficiently catalyzed by the Takemoto catalyst (XIX) to afford the spirodihydrocoumarins 81 in good yields (51-72%) and excellent enantioselectivities (Scheme 10.28). 

Companyo, X., Zea, A., Alba, A.-N. R., Mazzanti, A., Moyano, A., Rios, R., (2010). Organocatalytic synthesis of spiro compounds via a cascade Michael-Michael-aldol reaction. Chemical Communications, 46, 6953-6955. 

Cascade Michael-aldol reaction of mercaptobenzaldehyde with a,P-unsaturated oxazolidinone was realized by a cinchona-alkaloid catalyst (15b) to give benzoth-iopyran in high yields with excellent diastereoselectivity (Scheme 2.57). Contiguous three stereogenic centers were controlled [112]. 

Zhao and coworkers devised enantioselective syntheses of chiral cyclohexenones using primary-secondary diamine-catalyzed cascade reactions (Scheme 3.17). Diamine 13b promoted a cascade Michael-aldol-dehydration reaction between ketoester 77 and enones 78, affording highly functionalized chiral cyclohexenones 79 in good yields and with high enantioselectivities, although the diastereoselectiv-ity was poor [52]. The same group also applied a similar approach for an enantioselective synthesis of fluorinated cyclohexenones via Robinson annulation reaction [53]. 

Furthermore, this concept was extended to cascade Michael-addition/a-chlorination. Thus, a-chloro-)J-branched aldehydes 81 can be accessed with high degrees of stereoselectivities (Scheme 4.28) [110]. 

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],... 

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.

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