Electron Morita-Baylis-Hillman reaction

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. 

P-Amino carbonyl compounds containing an a-atkyUdene group are densely functionalized materials, which are widely applied in the synthesis of medicinal reagents and natural products [265]. These products are usually prepared through the classic aza-Morita-Baylis-Hillman reaction [176, 177] of activated imines and electron-deficient alkenes catalyzed by tertiary amines or phosphines. Chen and co-workers, in 2008, identified bis-thiourea 106 as a suitable catalyst for the... 

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... 

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. 

The allylic alcohol products from Morita-Baylis-Hillman reactions were shown to participate in a DMAP-mediated Tsuji-Trost-type reaction with /3-diketones or /3-ketoesters, forming the C-allylation product without requiring the use of palladium. Previously, it was shown that allylic alcohols combined with /8-ketoesters and DMAP afforded the transesterification products, in which the allylic alcohol displaced the ester substituent. The difference between these diverging reaction pathways is likely due to the electron-withdrawing group on the allylic alcohol in the MBH adducts vs. just alkyl substituents in the latter case. 

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. ... 

But, Yukawa et al. used lanthanum isopropoxide/BINOL system, 128, for the catalysis of asymmetric aza-Morita-Baylis-Hillman reaction (reaction 7.28), in which the electron-deficient alkenes, 129, reacted with... 

P-Stereogenic Ligands in Enantioselective Catalysis 8 Chemistry of the Morita-Baylis-Hillman Reaction 9 Proton-Coupled Electron Transfer A Carrefour of Chemical Reactivity Traditions... 

In the first step, the P-nucleophile adds to the Michael acceptor. The intermediate, bearing a negative charge on the a-carbon atom, then adds to the carbonyl group of the aldehyde. This 3-MCR approach may be an alternative to the Morita-Baylis-Hillman reaction. The interaction of tris(2-p3Tidyl)phosphine with electron-deficient allqmes in water as the solvent led to (J7)-pyridylvinylphosphine oxides in yields of 40-56% (Scheme 2). ... 

Another condensation-elimination sequence consists in a modification of the Morita-Baylis-Hillman reaction which provides dienes bearing an electron-withdrawing group (cyano or ester) in the 2-position 137 (Scheme 61) [122], Its mechanism begins as in a classical Morita reaction but a 1,2-proton shift occurs before the elimination of the phosphonium, leading to an intermediate ylide that condenses readily on a second aldehyde molecule. 

Nucleophilic amines or alkyl phosphines can mediate the addition of electron-deficient alkenes to reactive carbonyls such as aldehydes or ketones. This transformation, which affords functionalized allylic alcohols, is generally termed the Morita-Baylis-Hillman (MBH) reaction (Scheme 5.1) [1, 2]. 

The Morita-Baylis-Hillman (MBH) reaction can be broadly defined as a condensation of an electron-deficient alkene and an aldehyde catalyzed by tertiary amine or phosphine. Instead of aldehydes, imines can also participate in the reaction if they are appropriately activated, and in this case the process is commonly referred to as the aza-Morita-Baylis-Hillman (aza-MBH) reaction (Scheme 1.1). These operationally simple and atom-economic reactions afford a-methylene-p-hydroxy-carbonyl or a-methylene-p-amino-carbonyl derivatives, which consist of a contiguous assembly of three different functionalities. 

The aza-Morita-Baylis-HiUman reaction is known to be a useful and atom-economical C-C bond-forming reaction of electron-deficient alkenes with imines usually catalyzed by Lewis bases [202]. It formally involves a sequence of reactions including a Michael addition, a Mannich reaction, a proton transfer, and a retro-Michael reaction ( -elimination). Although there are many reports in the field of the enantioselective aza-Morita-Baylis-Hilhnan reaction, only rare examples of asymmetric domino reactions initiated by this reaction have been reported. In 2010, Sasai et al. [203] developed the first organocatalyzed asymmetric domino aza-Morita-Baylis-Hillman/aza-Michael reaction of a,p-unsaturated carbonyl compounds with N-tosylimines, allowing an easy access to chiral cis-1,3-disubstituted isoindolines as single diastereomers. The process was induced by a Hg-BINOL-derived catalyst and provided these products in high yields and enantioselectivities, as shown in Scheme 10.18. 

The Morita-Baylis-Hillman (MBH) reaction can be broadly defined as a coupling reaction between an alkene activated by an electron-vfithdrawing group and an electrophile that occurs under Lewis base catalysis, l,4-diazabicyclo[2.2.2]octane (DABCO) normally being used as the base (Scheme 3.1) [3]. 

We then investigated the CDC reaction between a-sp C-H bonds of nitrogen in THIQs and sp C-H bonds of electron-deficient alkenes. The reaction generated the Morita-Baylis-Hillman (MBH) reaction product by using l,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst (Scheme 1.11). Another common MBH catalyst, triphenylphosphine, was found to be nearly ineffective due to the generation of triphenylphosphine oxide during the reaction. 

Kinetic measurements and theoretical studies have been combined to develop new highly active catalysts for the aza-Morita-Baylis-Hillman (aza-MBH) reaction of electronically or sterically deactivated substrates, namely, ArCH=NTs. The electron-rich phosphines ArjP (Ar=4-MeOC6H4,4-Mc2NC6H4,4-Bu C6H4, etc.) and the DBU analogues, such as (356), were particularly successful... 

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