Michael aldol reactions

Michael additions followed by further Michael additions have become popular reactions and are usually referred to as Michael Michael Induced Ring Closure (MIM1RC) reactions. A three component Michael-Michael-aldol reaction of ketone enolates with acrylates can be achieved, resulting in the formation of six-membered ring compounds with good efficiency and high diastereoselectivites319. 

Scheme 2.7. Domino Mukaiyama/Michael/aldol reactions catalyzed by Sml2(THF)2.

Feringa s group has demonstrated that cyclopentene-3,5-dione monoacetals as 2-47 can also be successfully applied as substrates in an asymmetric three-component domino Michael/aldol reaction with dialkyl zinc reagents 2-48 and aromatic aldehydes 2-49 [17]. In the presence of 2 mol% of the in-sitw-generated enantiomeri-cally pure catalyst Cu(OTf)2/phosphoramidite 2-54, the cyclopentanone derivatives 2-51 were formed nearly exclusively in good yields and with high ee-values (Scheme 2.11). 

Scheme 2.21. Domino Michael/aldol reactions of 7-keto-2-enimides 2-93.

An impressive organocatalytic asymmetric two-component domino Michael/ aldol reaction has been recently published by Jorgensen and coworkers (Scheme 2.23) [38]. 

Scheme 2.23. Domino Michael/aldol reaction of a,(5-unsaturated ketones with (3-ketoesters.

Krische and coworkers [44] developed a Rh-catalyzed asymmetric domino Michael/aldol reaction for the synthesis of substituted cyclopentanols and cyclohex-anols. In this process, three contiguous stereogenic centers, including a quaternary center, are formed with excellent diastereo- and enantioselectivity. Thus, using an enantiopure Rh-BINAP catalyst system and phenyl boronic acid, substrates 2-108 are converted into the correspondding cyclized products 2-109 in 69-88% yield and with 94 and 95% ee, respectively (Scheme 2.24). 

T. Arai, H. Sasai, K. Aoe, K. Okamura, T. Date, M. Shibasaki, A New Multifunctional Heterobimetallic Asymmetric Catalyst for Michael Additions and Tandem Michael-Aldol Reactions, Angew. Chem. Int. Ed Engl 1996, 35,104-106. 

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. 

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

Scheme 41 Divergent domino Michael/aldol reaction...

Scheme 6.71 Succinimide-containing substituted thiochromanes obtained from the 12-catalyzed enantio- and diastereoselective domino Michael-aldol reaction between 2-mercaptobenzaldehydes and maleimides.

In 2007, Wang and co-workers published a protocol for an enantio- and diastereoselective domino Michael-aldol reaction using electron-rich and electron-deficient 2-mercaptobenzaldehydes and maleimides as substrates [223]. The conversion was described to proceed smoothly in the presence of bifunctional catalyst 12 (lmol% loading) in xylenes at 0°C reaction temperature producing the desired chiral succinimide-containing substituted thiochromanes 1-5 in high yields (83-96%), in synthetically useful ee values (74—94%), and diastereoselectivities (up to dr 20 1) in 7h reaction time (Scheme 6.71). 

Michael-aldol reactions.1 In the presence of (C6H5)3CC104, the conjugate adducts of silyl enol ethers to enones can undergo aldol reactions to provide y-acy 1-8-hydroxy ketones. 

Figure 8D.7. Proposed Mechanism for the Catalytic Asymmetric Tandem Michael-Aldol Reaction Promoted by ALB.

Optically active 4-alkoxycarbonyl-3-hydroxycyclohexanones (formed in highly enantio- and diastereoselective organocatalytic asymmetric domino Michael aldol reaction of / -keto esters and a,/ -unsaturated ketones) are transformed into corresponding chiral oxepanones under the action of urea-hydrogen peroxide and trifluoroacetic anhydride <2004AGE1272>. 

A new tandem Michael-aldol reaction of a,ft-unsaturated compounds bearing a chalcogenide or thioamide group with electrophiles has been reviewed.163 The product o -(o -hydroxyalkyl)enones - Morita-Baylis-Hillman (MBH) adducts - can be formed with significant stereocontrol when an optically active thione is used. 

Diketone (72) undergoes an acid-catalysed Michael-aldol reaction to give tricyclic ketone (73).205... 

Three-component Tandem Michael-Aldol Reaction I 281... 

Shibasaki and co-workers [19] reported a catalytic asymmetric tandem Michael-aldol reaction wherein cylopentenone 50, diethylmalonate, and 3-phenylpropanal react in the presence of Al-Li-(R)-BINOL complex catalyst 57 forming the corre-... 

Scheme 9.10. Catalytic enantioselective tandem Michael-aldol reaction.

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

Unusual -branched Baylis-Hillman adducts have been prepared by Li and coworkers by a novel Et2AlCl promoted domino Michael-aldol reaction of propynoates 50 with organo-cuprates and chiral p-toluenesulfinimines 52 (Scheme 10) [42], These condensations proceeded with very good diastereoselectivity to give allylic amines 53. The selectivity can be explained through the chairlike transition state 54. The anion intermediate approaches the sulfinimine from the sterically less hindered side of the lone pair of electrons. The nucleo-... 

Scheme 10. Domino Michael-aldol reaction of propynoates with organocuprates and chiral p-toluenesulfinimines (Li et a .).

Moderate yields of 3-hydroxyalkylthiochromones 521 result from a tandem Michael-aldol reaction of l-(2-methyl-s111 I d n y I phenv l)propvnone with aldehydes in the presence of two moles of BF3 etherate as a Lewis acid. The process involves a 6-emfo-dig cyclization (Equation 181) <2002TL7039, 2005PS(180)989>. 

A tandem Michael-aldol reaction of ynone selenides with aldehydes provides a convenient route to 3-substituted selenochromen-4-ones 132 (Equation 49) <2002TL7039>. The reaction proceeds via an intermediate zwitterion formed via a 6-/ r/ -r//g-cyclization. 

Guimaraes CRW, M Udier-Blagovic, WL Jorgensen (2005) Macrophomate synthase QM/MM simulations address the Diels-Alder versus Michael-Aldol reaction mechanism. J. Am. Chem. Soc. 127 (10) 3577-3588... 

This sequential process of Michael-aldol reaction leading to a new six-membered ring is known as the Robinson annelation. It was, in fact, Robinson who invented the idea of using a Mannich product in conjugate additions because he wanted to develop this important reaction. There are now thousands of examples used to make all kinds of compounds, especially steroids (Chapter 49). 

An intramolecular tandem Michael aldol reaction was described for esters that have an enolizable aldehyde in the molecule. The lithium ester enolate generated through the Michael reaction undergoes an intramolecular aldol reaction. Thus, the reaction of unsaturated esters 153 with lithium benzylthiolate provided the expected cyclization products 156 and 157 via (w-formylenolate 154 in an excellent cis stereoselectivity (Scheme 49)no. 

The reaction of salicylaldehydes with a,P-unsaturated compounds which can lead to chromenes, chromans and other heterocycles has been reviewed <07OBC1499> and details of their reaction with allenic esters and ketones have been published <07CEJ3701>. A proline-catalysed benzoic acid-promoted asymmetric synthesis of chromene-3-carbaldehydes involves a domino oxa-Michael - aldol reaction with a,P-unsaturated aldehydes the ee range is 83-98% (Scheme 11) <07CEJ574>. 

---