Michael/Morita-Baylis-Hillman

An interesting alternative intramolecular cyclisation was discovered by Jprgensen and co-workers [187]. Although not strictly exploiting an enamine intermediate, the transformation represents a secondary amine catalysed Morita-Baylis-Hillman reaction leading to a series of highly functionalised cyclohexene products. Reaction of the Nazarov reagent 137 with a,P-unsaturated aldehydes in the presence of the diarylprolinol ether 30 led to the cyclohexene products 138 (49-68% yield 86-96% ee) via a tandem Michael/Morita-Baylis-Hillman reaction (Scheme 54). 

Scheme 54 Organocatalytic Michael/Morita-Baylis-Hillman reaction...

Scheme 7.28 Enantioselective Michael/Morita-Baylis-Hillman cascade reaction.

Chiral cyclohexene derivatives were also constructed by an asymmetric four-component quadruple domino reaction initiated by oxa-Michael addition of alcohols to acrolein. The other two components were another equivalent of acrolein and a nitroalkene. Enders has shown that cyclohexene derivatives can also be assembled by a domino reaction of y-nitroketones and enals. Domino Michael/aldol condensation of 5-oxoalkanals and a,p-unsaturated aldehydes afforded densely functionalised cyclohexenes. Combination of unsaturated aldehydes with unsaturated p-ketoesters resulted in the formation of chiral cyclohexene derivatives via a Michael/ Morita-Baylis-Hillman sequence (Scheme 8.21). ... 

Scheme 8.21 S5mthesis of q clohexene derivatives via Michael/Morita-Baylis-Hillman sequence.

A similar reaction was also reported by Jprgensen s group regarding the addition of Nazarov reagents (75) to enals (15). The reaction furnishes highly substituted cyclohexanones in high yields and stereoselectivities via an organocatalytic tandem Michael/Morita-Baylis-Hillman reaction catalyzed by the diphenylprolinol derivative VII [50]. 

Scheme 2.30 Tandem Michael-Morita-Baylis-Hillman -Knoevenagel reaction catalysed by a chiral diarylprolinol trimethylsilyl ether and L-proline.

Interestingly, [3 + 3] reaction of a,p-unsaturated aldehydes with 185 bearing single nucleophilic site also proved to be feasible through a Michael-Morita-Baylis-Hillman sequence catalyzed by a chiral secondary amine (Scheme 1.80) [125]. The reaction proceeds in high enantio- and diastereoselectivity for a wide range of a,P-unsaturated aldehydes and p-keto esters. 

The following subsections discuss the use of ohgopeptides in aldol, Michael, Morita-Baylis-Hillman, and the hydrocyanation of aldehydes. 

Also known as Morita-Baylis-Hillman reaction, and occasionally known as Rauhut-Currier reaction. It is a carbon—carbon bond-forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be aldehydes, a-alkoxycarbonyl ketones, aldimines, and Michael acceptors. 

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. 

A study of the effect of the Michael acceptor configuration on the efficiency of intramolecular Morita-Baylis-Hillman reactions has been performed. Enones containing a pendant aldehyde moiety attached at the -position of the alkene group were employed as substrates and the reactions were catalysed by a phosphine. In all cases examined, with Ph3P as the catalyst, cyclization of (Z)-alkene (117) gave 2.5-8.5 times higher yield than with the E-isomer (115) under identical reaction conditions, both affording the same product (116). Steric effects are believed to be the source of this difference in reactivity.172... 

Asymmetric aza Morita-Baylis-Hillman reactions of N-sulfonylimines or N-sulfinimines with Michael accepters in the presence a Lewis base catalyst to give the corresponding chiral a-methylene-/ -amino compounds have been described [27]. 

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... 

Furthermore, following an analogous methodology, combining the Morita-Baylis-Hillman reaction and the Trost-Tsuji reaction, Krische and co-workers have obtained allyl-substituted cyclopentenones 94 [84], Reaction was initiated by Michael addition of tributyl phosphine to an enone moiety 92, generating a latent enolate 93 which reacts intramolecularly with a jr-allylPd complex as the electrophile partner. A final -elimination step of trib-utylphosphine, favored by the presence of the methoxide ion, delivered the substituted cyclopentenones 94 (Scheme 36). 

As shown in Equation (17), 2-trimethylsilyloxyfuran also participated in a triphenylphosphine-catalyzed substitution reaction with Morita-Baylis-Hillman acetates to provide interesting 7-butenolides regio- and diastereoselec-tively <2004AGE6689>. However, the reaction mechanism (vinylogous Michael vs. Diels-Alder) has not been distinguished. 

The Morita-Baylis-Hillman reaction and its aza-variant - the reaction of an electron-deficient alkene with an aldehyde (MBH) or an imine (aza-MBH) - provide a convenient route to highly functionalized allylic alcohols and amines. This reaction is catalyzed by simple amines or phosphines, which can react as a Michael donor with an electron-deficient alkene, generating an enolate intermediate. This intermediate in turn undergoes the aldol or Mannich reaction with electrophilic C=0 or C=N bonds, respectively, to deliver allylic alcohols and amines. 

In 2007, Jorgensen and coworkers also reported the anti-Michael reaction of the cyclic P-ketoesters 53 with the sulfone group-substituted acrylonitrile 54 under PTC conditions (52 (6mol%), CHC13, aq Cs2C03 or K3P04) [15]. As depicted in Scheme 9.18, the sulfone group of the acceptor directed the nucleophile and then is removed to afford the anti-Michael (a-addition Morita-Baylis-Hillman-like) adducts 55 in variable yields (42-90%) and ee values (60-94% ee) (Scheme 9.18). 

Chen and coworkers published a formal [3 + 3]-type reaction to give highly substituted cyclohexenes 8. This domino process consists of an allylic-allylic alkylation of an a,a-dicyanoalkene derived from 1-indanone and Morita-Baylis-Hillman carbonates, following an intramolecular Michael addition, by employing dual orga-nocatalysis of commercially available modified cinchona alkaloid (DHQD)2AQN If (hydroquinidine (anthraquinone-l,4-diyl) diether) and (S)-BINOL. The cyclic adducts... 

Scheme 13.26 Model proposed to explain the origin ofthe enantioselectivity. (Source E.L. Myers. J.C. de Vries, V.K. Aggarwal, Reactions of iminium ions with Michael acceptors through a Morita Baylis Hillman...

The Morita-Baylis-Hillman reaction is, in general, a carbon-carbon bondforming reaction of an a,(3-unsaturated compound with an aldehyde mediated by an organic nucleophilic base resulting in the formation of an allylic alcohol. Morita reported the use of a phosphine as catalyst and Baylis and Hillman used a tertiary amine. Variation of the electrophile to electron-deficient alkenes in a Michael-Michael elimination sequence leads to homo- and heterodimerisation and is known as the Rauhut-Currier reaction. The electrophilic aldehyde could be substituted by an imine or derivative in the aza-Morita-Baylis-Hillman reaction. Recently, there has been an increase in the use of this reaction for the construction of many different targets using many different amine derived catalysts. Scheme 2.2 shows a general view of this reaction and the accepted mechanism. ... 

---