Phosphines Morita-Baylis-Hillman-reaction

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... 

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... 

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... 

According to another NMR study, the mechanism of bifunctional activation in the asymmetric aza-Morita-Baylis-Hillman reaction (Scheme 7) involves rate-limiting proton transfer (116) in the absence of added protic species155 (in consonance with the report summarized in Scheme 5144), but exhibits no autocatalysis. Addition of Brpnsted acids led to substantial rate enhancements through acceleration of the elimination step. Furthermore, it was found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the reaction product by proton exchange at the stereogenic centre. This behaviour indicates that the spatial arrangement of a bifunctional chiral catalyst for the asymmetric aza-Morita-Baylis-Hillman reaction is crucial not only for the stereodifferentiation within the catalytic cycle but also for the prevention of subsequent racemization.155... 

Asymmetric organocatalytic Morita-Baylis-Hillman reactions offer synthetically viable alternatives to metal-complex-mediated reactions. The reaction is best mediated with a combination of nucleophilic tertiary amine/phosphine catalysts, and mild Bronsted acid co-catalysts usually, bifunctional chiral catalysts having both nucleophilic Lewis base and Bronsted acid site were seen to be the most efficient. Although many important factors governing the reactions were identified, our present understanding of the basic factors, and the control of reactivity and selectivity remains incomplete. Whilst substrate dependency is still considered to be an important issue, an increasing number of transformations are reaching the standards of current asymmetric reactions. 

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). 

A NHC-catalyzed aza-Morita-Baylis-Hillman reaction (aza-MBH) following a standard nucleophile-mediated MBH mechanism has been disclosed very recently (He et al. 2007). Although combined with a preceding equilibrium for the reversible formation of imine-carbene adducts this reaction has similarities with phosphines and their organo-catalytic reactivity (Methot and Roush 2004). 

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 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. ... 

It is well known that the Morita-Baylis-Hillman reaction originated from the phosphine-catalyzed dimerization of activated olefins reported by Rauhut and... 

Scheme 127 Phosphine-catalyzed Morita-Baylis-Hillman reaction in the total synthesis of (—)-spinosyn A (614)...

On the other hand, an axially chiral phosphine alcohol organocatalyst was successfully employed by Shi and Liu to promote the aza-Morita-Baylis-Hillman reaction between A -(arylmethylidene)arylsulfonamide and methyl vinyl ketone, providing the corresponding adducts in moderate to good yields (26-85%) and high enantioselectivities of up to 94% ee, when used at 10 mol % of catalyst loading in Furthermore, these authors have shown that the... 

Scheme 3.30 Aza-Morita-Baylis-Hillman reactions catalysed by polyether dendritic phosphine.

Shi, Y.-L. Shi, M. Ghiral Thiourea-Phosphine Organocatalysts in the Asymmetric Aza-Morita-Baylis-Hillman Reaction. Adv. Synth. Catal. 2007, 349,2129-2135. 

The L-threonine-derived phosphine-sulfonamide (23) is one of the best catalysts for the enantioselective aza-Morita-Baylis-Hillman reaction. A DPT study has identified ( ) a key intramolecular N-H—O hydrogen-bonding interaction between the sulfonamide... 

Recent advances in organocatalytic asymmetric Morita-Baylis-Hillman reactions and their aza-variants have been reviewed (112 references), with a particular focus on amine- and phosphine-catalysed routes, and bifunctional catalysis. 0... 

The cooperative effect of Brpnsted acid catalysts and thiourea catalysts has been noticed by the Shi group (Fig. 18) [74]. In their 2007 paper on chiral thiourea-phosphine catalyzed asymmetric aza-Morita-Baylis-Hillman reaction, Shi and co-workers described that when they used a freshly prepared 77-benzylidene-4-methylbenzenesulfonamide substrate, much lower yield and enantioselectivity of the aza-Morita-Baylis-Hillman product was obtained compared with their initial result when using a long-stored substrate. They subsequently found that the long-stored substrate contained a small amount of 4-methylbenzenesulfonamide and... 

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). ... 

NHC catalyzed reactions have been expanded to include reactions such as aza-Morita-Baylis-Hillman and Mnkaiyama aldol reactions. Ye and co-workers illustrate the utility of NHCs in a reaction that is traditionally catalyzed by amines and phosphines (Scheme 52) [169],... 

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

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 is an important 100% atom economic transformation that allows the formation in one step of a flexible allylic alcohol motif. Efforts in this field have been directed recently to the solution of two problems to enhance the generally sluggish reaction rate and to achieve asymmetric catalytic versions. Scheme 1.15 gives the catalytic cycle of the MBH reaction. The catalyst is a highly nucleophilic tertiary amine, generally DABCO, or a tertiary phosphine, which adds to the oc,P-unsaturated electrophile in a 1,4 fashion to deliver an enolate that, in turn, adds to the aldehyde. A critical step is the proton transfer from the enolizable position to the oxygen atom this process is catalysed by an alcohol that plays the role of a proton shuttle between the two positions. Water has also been reported to strongly speed up the reaction at a well-defined concentration. Moreover, the... 

AT-Tosylaldimmes 293 reacted with excess allene 294 in the presence of tertiary phosphine promoters to give a mixture of 295 (major) and 296 (minor). The normal Morita-Baylis-Hillman adducts 297, which were formed on catalysis by DMAP, were not intermediates in the formation of the piperidines. A mechanistic rationale for the different reactions was presented (Scheme 89) 050BC3686>. 

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