Morita-Baylis-Hillman reaction catalyst

Scheme 51 Morita-Baylis-Hillman reaction using the dual catalysts 130 and 58...

The most efficient catalyst system for the Morita-Baylis-Hillman reaction of methyl vinyl ketone has been reported by Miller [183, 184], Use of L-proline (58) (10 mol%) in conjunction with the A-methyl imidazole containing hexapeptide 131 (10 mol%) provided an efficient platform for the reaction of 125 with a series of aromatic aldehydes 127 (52-95% yield 45-81% ee) (Scheme 52). Importantly, it was shown that the absolute configuration of the proline catalyst was the major factor in directing the stereochemical outcome of the reaction and not the complex peptide backbone. 

Intramolecular versions of the Morita-Baylis-Hillman reaction have also met with success using a dual Lewis acid/Lewis base catalyst system. Miller has shown that a combination of A-methyl imidazole (132) (10 mol%) and... 

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... 

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... 

A A /V /V -Tetramethylelhylcncdiaminc (TMEDA) as catalyst of the Morita-Baylis-Hillman reaction has been found to be more efficient than DABCO in aqueous media.146 1-Methylimidazole 3-/V-oxide promotes the Morita-Baylis-Hillman reaction of various activated aldehydes with ,/i-unsaturated ketones and esters CH2= CHCOR (R = Me, OMe) in solvent-free systems.147 In another study, the Morita-Baylis-Hillman reaction has been successfully performed under aqueous acidic conditions at pH 1, using a range of substrates and tertiary amines as catalysts.148... 

Another class of bifunctional organocatalysts for the enantioselective aza-Morita-Baylis-Hillman reaction of imines (112) with enones (113) (Scheme 6) is based on BINOL (115). The efficiency of the catalysts proved to be mainly influenced by the position of the Lewis basic moiety attached to the BINOL scaffold. The activation of the substrate by acid-base functionalities and the fixing of conformation of the catalyst (115) are apparently harmonized to maximize the enantiocontrol (<95% ee) 52... 

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... 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

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. 

In the Morita-Baylis-Hillman reaction, enolate intermediates are formed by addition of a nucleophilic catalyst to an a, 3-unsaturated carbonyl compound. These intermediates can be trapped with a variety of electrophiles,402 including azodicarboxylic esters (Eq. 102).403 The reaction fails with ethyl acrylate. 

Some of the catalyst systems used in the asymmetric aldol reaction are also effective in related reactions. Thus, bifunctional catalysts and L-prohne-based organocatalysts have been used to good effect in the nitroaldol reaction and Mannich reaction. The latter process is also effectively catalysed by enantiomeri-cally pure Bronsted acids. Furthermore, much recent progress has been made in the development of a catalytic asymmetric Morita-Baylis-Hillman reaction using Lewis/Bronsted acid catalysts and bifunctional catalysts. 

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. ... 

There have been only a few reports on asymmetric versions of the intramolecular MBH reaction Scheme 1.105 shows one representative example. The intramolecular Morita Baylis Hillman reaction has been achieved with unprecedented levels of enantioselectivity by using a co-catalyst system involving pipecolinic acid and iV-methylimidazole cyclic MBH products 289 were... 

Polymer-supported Catalysts for the Morita-Baylis-Hillman Reaction... 

In 2005, Wang and coworkers reported a new bifunctional binaphthyl-derived amine thiourea 16 as an efficient organocatalyst for the Morita-Baylis-Hillman reaction of cyclohexenone with aliphatic, aromatic and sterically hindered aldehydes. The design of the catalyst follows Takemoto s design of a bifunctional motif. This catalytic protocol provided access to useful chiral allylic alcohol building blocks in high yields and high enan-tioselectivities (Scheme 19.21). 

In 2006, Berkessel and coworkers reported a new and improved iso-phoronediamine-derived bisthiourea organocatalyst for the asymmetric Morita-Baylis-Hillman reaction. Employing 20 mol% of catalyst 67 and N,iV,iV, iV -tetramethylisophoronediamine (TMIPDA) as base under neat reaction conditions, the adduct of 2-cyclohexen-l-one with cyclohex-anecarbaldehyde was obtained in 75% yield and 96% enantiomeric excess... 

Scheme 22.3 Asymmetric aza-Morita-Baylis-Hillman reaction catalysed by Sasai s bifunctional chiral pyridine catalyst.

Scheme 22.4 Asymmetric aza-Morita-Baylis-Hillman reaction between imine and allenoate catalysed by Miller s peptide-based pyridine catalyst.

Miller extended the scope of the aza-Morita-Baylis-Hillman reaction by employing highly functionalised allenoate 26 as a,p-unsaturated carbonyl component. Catalyst 24 effectively converted racemic trisubstituted allene 26 to tetrasubstituted allene 27 in up to 42 1 diastereomeric ratio and 88% enantiomeric excess (Scheme 22.5). 

Peptide-based imidazole catalyst 63 in the presence of L-proline as a cocatalyst promoted asymmetric Morita-Baylis-Hillman reactions between methyl vinyl ketone and aromatic aldehydes (Scheme 22.14). The combination... 

Scheme 22.14 Asymmetric Morita-Baylis-Hillman reaction catalysed by a cocatalyst system consisting of peptide catalyst 63 and t-proline.

Among all catalysts containing phenol groups, the best results in terms of yields and asymmetric inductions were obtained with molecules containing a binaphthol scaffold. Inspired by the seminal work of Yamada et on the Morita-Baylis-Hillman reaction between cyclic enones and aldehydes promoted by a cooperative catalytic system of tributylphosphine and phenols (including rac-BINOL), McDougal and Schaus reported the first example of an asymmetric Morita-Baylis-Hillman reaction using chiral BINOL and binaphthol derivatives 38 as catalysts, in the presence of triethylphosphine as nucleophilic promoter (Scheme 24.15). 

Scheme 24.15 Catalytic asymmetric Morita-Baylis-Hillman reaction with modified BINOL catalysts.

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