The Morita-Baylis-Hillman Reaction

The reaction of 4-95 to give a 96 4-mixture of 4-96 and 4-97 containing the central core of 4-94 was performed by heating 4-95 for 67 h at 40 °C and then adding PMe3 to induce the Morita-Baylis-Hillman reaction (Scheme 4.21). 

Fig. 11 Proposed catalytic cycle for the Morita-Baylis-Hillman reaction...

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... 

The Morita-Baylis-Hillman reaction can be accelerated by a catalytic amount of lithium bromide and l,8-diazabicyclo[5.4.0]undec-7-ene in a solvent-free medium.171... 

Using electrospray ionization mass spectrometry in both positive and negative ion modes, the on-line scanning of the Morita-Baylis-Hillman reaction in the presence of imidazolium ionic liquids has been investigated. The interception of several supramolecular species indicated that ionic liquids co-catalyse the reactions by activating the aldehyde toward nucleophilic enolate attack and by stabilizing the zwitterionic species that act as the main intermediates.175... 

Methylimidazole 3-A-oxide (49) catalyses the Morita-Baylis-Hillman reaction at room temperature under solvent-free conditions addition to the enone reactant to give a zwitterionic enolate (50) is proposed, followed by reaction with aldehyde.177... 

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... 

In a different study, based on the reaction rate data collected in aprotic solvents, the Morita-Baylis-Hillman reaction has been found to be second order in aldehyde and first order in DABCO and acrylate. On the basis of these data, a new mechanism has been proposed, involving a hemiacetal intermediate (110). The proposed mechanism is further supported by two different kinetic isotope effect experiments.145... 

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... 

The Morita-Baylis-Hillman reaction of chiral glyoxylic acid derivatives with cyclic a,/ -unsaturated ketones proceeded under the catalytic influence of dimethyl sulfide in the presence of titanium tetrachloride [27]. The adducts were obtained with high diastereomeric excess (>95% de) and typical yields around 80%. 

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). 

Bicyclic azepine 33 was formed by the conjugate addition of a piperidine to a tethered a,P-unsaturated ester 32 which was formed by the Morita-Baylis-Hillman reaction of the corresponding aldehyde 31 <07JOC5608>. 

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 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. 

The Catalyzed a-Hydroxylation and a-Aminoalkylation of Activated Olefins (The Morita-Baylis-Hillman Reaction) Engelbert Ciganek... 

Addition of benzaldehyde led to a Pt-catalyzed three-component coupling related to the Morita-Baylis-Hillman reaction, which could be explained mechanistically in terms of competition for the zwitterionic nucleophile 16 between an external electrophile (benzaldehyde) and an internal one (Pt-H). Consistent with this idea, increasing the concentration of benzaldehyde led to a larger ratio of 17-18 (Scheme 27) [45]. 

At the same time as new applications of ionic liquids are discovered on almost a daily basis, limitations of these reaction media are also uncovered. While studying the Morita-Baylis-Hillman reaction in ionic liquids, Aggarwal observed that [bmim][Cl] was deprotonated by the weak base present in the reaction mixture, leading, after reaction with benzaldehyde, to salt 111 (Scheme 49). Deprotonation of imidazolium salts with strong bases (KCyBu or NaH) is well known, providing, for example, an easy route to Pd-carbene complexes (Section 2.3.5.1). However, this observation limits the use of imidazolium-based ionic liquids even in weakly basic conditions, where they can react with electrophiles. It also explains previous works reporting low yields for reactions performed in these conditions, such as the Horner-Wadsworth-Emmons reaction in [emimlCPFe] or [emim][BF4]. ... 

Significant rate enhancement of the Morita-Baylis-Hillman reaction through solid-state milling has been noted by Mack et al. (Scheme 2.44). [39], In such conditions, Baylis-HiUman products 130 were obtained in up to >98% yield in as little as 0.5 h by solvent-free reaction of p-nitrobenzaldehyde 129 and methyl acrylate 128. Various bases were tested and l,4-diazabicyclo[2.2.2]octane (DABCO) showed the best performance (Table 2.41). Other p-substimted aromatic aldehydes reacted with methyl acrylate much slower, within 9 5 h and lower yields (28-97%) were obtained. This represents one of the fastest methods of Bayhs-Hilhnan reactions under neat conditions. One of the main drawbacks of this reaction carried out in classical conditions is its slow rate, which has been shown typically to take days to weeks to produce adequate product yields. 

Mack J, Shumba M. Rate enhancement of the Morita-Baylis-Hillman reaction through mechanochemistry. Green Chem 2007 9 328-30. 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

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. ... 

Also known as the Morita-Baylis-Hillman 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. 

During the past 40 years, the Morita-Baylis-Hillman reaction has seen exponential growth in terms of three components, that is, the activated olefins. 

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