Aldol Morita-Baylis-Hillman reaction

An intramolecular vinylogous Morita-Baylis-Hillman reaction, followed by intramolecular aldol cyclization,129 is described under Intramolecular Aldols above. 

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. 

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. 

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. ... 

Phosphonium salts may be intermediates in different reactions. The Morita-Baylis-Hillman reaction follows such a protocol. In a typical reaction sequence, a,P-unsaturated carbonyl compounds react with aldehydes in the presence of nucleophiles, such as a trialkylphosphine, to afford aldol-like products (Scheme 75/1), while in another example, unsaturated carbonyl compounds with bromo atom at the end of the chain are cyclized to cycloalkene derivatives (Scheme 75/2). In both... 

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],... 

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. 

The reagent in Step 1, (E)-2-methyl -2-hexen-l-ol, was prepared using a modified Morita-Baylis-Hillman procedure with ethyl acrylate and l,4-diazabicyclo[2.2.2]octane. Other examples of the Bayliss-Hilman reaction are provided (1). The stereoisomer, (Z)-2-methyl-2-hexen-l-ol was used to prepare other aldol stereoisomers. The preparation of the (Z)-isomer is provided below by the author ... 

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). ... 

Li and co-workers developed a novel asymmetric halo aldol reaction using Evans oxazolidinones as chiral auxiliaries for tandem I-C/C-C bond formations. This reaction provides a practical approach to a variety of halo aldols of a non-Evans type that cannot be easily prepared by other methods. Excellent diastereoselectivity (> 95% de) and yields (80-93%) have been obtained. This reaction can be considered as a Lewis acid (Et2Al-I)-promoted Morita-Baylis-Hillman (MBH) process. 

Shibasaki et al. also reported that similar Morita-Baylis-Hillman-type products were obtained via asymmetric aldol reaction of a p,y-unsaturated ester with aldehydes using a chiral barium catalyst system (Table 3) [25]. The desired products formed in good yields with high enantioselectivities after isomerization. Several aromatic- and alphatic aldehydes were tested, and in all cases high a-(E) selectivities and high enantioselectivities were observed. Several aryl, heteroaryl, alkenyl, and alkyl aldehydes can be used as substrates in this reaction. 

Sasai has recently described an interesting entry into chiral tetrahydropyridines 37 from acrolein and aromatic tosylimines [29], which involves an enantioselective version of a domino process previously reported by Huang [30] that can be classified as an ABB multicomponent reaction because of the participation of two molecules of acrolein, each of them with a different role in the overall transformation. The best results were obtained with catalyst 36, which contains both Lewis base and Brpnsted acid structural fragments, and the reaction was rationalized as the result of an aza Morita-Baylis-Hillman/aza Michael/aldol sequence (Scheme 3.8). 

In the classical Morita-Baylis-Hillman (MBH) reaction an a,P-unsaturated ester (electrophilically activated alkene), is activated by the reversible Michael-addition of a tertiary amine catalyst (e.g. DABCO), producing a zwitterion intermediate, the enolate moiety of which can react with an aldehyde to form an aldolate zwitterion. Retro-Michael-addition then regenerates the catalyst and the MBH-product (Scheme 7.22). The catalyst is sometimes used in high amounts (over stoichiometric) and often the reaction is very sensitive to the Michael acceptor used. 

The Morita-Bayhs-Hillman (MBH) reaction involves the conversion of an a,p-imsaturated carbonyl compound into an aldol-like adduct. The reaction is catalysed by tertiary amines (7.155), which form an intermediate enolate (7.157) by conjugate addition (rather than by direct deprotonation of the a-proton). The enolate imdergoes an aldol reaction with an aldehyde (7.01), followed by loss of the amine catalyst to provide the Baylis-Hillman adduct (7.158), as shown in Figure 7.7. 

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