And the Baylis-Hillman reaction

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

An alkene activated by an electron-withdrawing group—often an acrylic ester 2 is used—can react with an aldehyde or ketone 1 in the presence of catalytic amounts of a tertiary amine, to yield an a-hydroxyalkylated product. This reaction, known as the Baylis-Hillman reaction, leads to the formation of useful multifunctional products, e.g. o -methylene-/3-hydroxy carbonyl compounds 3 with a chiral carbon center and various options for consecutive reactions. 

Together with a shift of the proton from the a-carbon to the alkoxide oxygen, the tertiary amine is eliminated from the addition product to yield the unsaturated product 3. Early examples of the Baylis-Hillman reaction posed the problem of low conversions and slow reaction kinetics, which could not be improved with the use of simple tertiary amines. The search for catalytically active substances led to more properly adjusted, often highly specific compounds, with shorter reaction times." Suitable catalysts are, for example, the nucleophilic, sterically less hindered bases diazabicyclo[2.2.2]octane (DABCO) 6, quinuclidin-3-one 7 and quinuclidin-3-ol (3-QDL) 8. The latter compound can stabilize the zwitterionic intermediate through hydrogen bonding. ... 

An intramolecular variant of the Baylis-Hillman reaction is also possible, and may be used for the construction of functionalized ring systems, e.g. a cyclopen-tene derivative such as 12. However, good yields have been achieved in only a few cases ... 

In the presence of a base such as l,4-diazabicyclo[2.2.2]octane (DABCO) or tri-alkylphosphines, conjugated carbonyl compounds such as esters and amides add to aldehydes via the a-carbon to give a-alkenyl-P-hydroxy esters or amides. This sequence is called the Baylis-Hillman reaction and a simple example is... 

The asymmetric Baylis-Hillman reaction of sugar-derived aldehydes as chiral electrophiles with an activated olefin in dioxane water (1 1) proceeded with 36-86% de and in good yields of the corresponding glycosides (Eq. 10.47).104 The use of chiral /V-mcthylprolinol as a chiral base catalyst for the Baylis-Hillman reaction of aromatic aldehydes with ethyl acrylate or methyl vinyl ketone gave the adducts in good yields with moderate-to-good enantioselectivities in l,4-dioxane water (1 1, vol/vol) under ambient conditions.105... 

PDMS thimble contained in glass vial. The substrate, an acetal, is within the PD MS thimble and undergoes an acid-catalyzed transformation into an aldehyde. The aldehyde then diffuses to the exterior and undergoes the Baylis—Hillman reaction catalyzed by DMAP to give the product, (b) Various acid and base... 

In the next step of the sequence, the authors sought to introduce a hydroxy-methylene substituent at the unsubstituted 7-position of the enone. This bond construction can be carried out by conducting a Baylis-Hillman reaction with formaldehyde. In this instance, the authors used a modification of the Baylis-Hillman reaction which involves the use of a Lewis acid to activate the enone [26]. Under these conditions, the enone 42 is treated with excess paraformaldehyde in the presence of triethylphosphine (1 equiv), lanthanum triflate (5 mol%), and triethanolamine (50 mol%). It is proposed that the lanthanum triflate forms a complex with the triethanolamine. This complex is able to activate the enone toward 1,4-addition of the nucleophilic catalysts (here, triethylphosphine). In the absence of triethanolamine, the Lewis acid catalyst undergoes nonproductive complexation with the nucleophilic catalyst, leading to diminution of catalysis. Under these conditions, the hydroxymethylene derivative 37 was formed in 70 % yield. In the next step of the sequence, the authors sought to conduct a stereoselective epoxidation of the allylic... 

Alkyl 2-(hydroxymethyl)acrylates are versatile functionalized monomers and synthetic building blocks. Conventional preparations employ the Baylis-Hillman reaction which involves the addition of formaldehyde to the parent acrylate ester, catalyzed by l,4-diazabicyclo[2.2.2]octane (DABCO). These reactions typically take several days at room temperature, but can be achieved within minutes in the CMR and MBR (Scheme 2.4). Rapid heating under pressure prevents loss of formaldehyde. Subsequent cooling limits hydrolysis of the product, as well as dimerization and polymerization [33],... 

Methylmagnesium bromide (191) exerts a great influence on the stereoselectivity of the reactions between mesitonitrile oxide 10 and the Baylis-Hillman adducts 192. In the absence of a Grignard reagent, a mixture of isomers is formed in which compounds 194 are the main products. The presence of a Grignard reagent reverses the stereoselectivity (Scheme 9.59). When Fisera [107] performed these reactions under microwave irradiation, the reaction times decreased from days to less than 5 min without any loss of stereoselectivity for noncatalyzed cycloadditions, but with a small change in the stereoselectivity in the chelated reactions. 

Chiral fe-thiourea-type catalysts effectively provide the Baylis Hillman reaction with cyclohexenone and aldehydes.181 In several reactions, thiourea derivatives have been used as significant and specific catalyst because of their intermolecular hydrogen bonding ability (Scheme 74).182 186... 

Hydroxyazetidin-2-ones can be oxidised efficiently to azetidine-2,3-diones by P205 in DMSO <00JPR585>, and then the 3-carbonyl group can be alkylated stereoselectively by application of the Baylis-Hillman reaction <99TL7537> or by use of substituted propargyl bromides to provide densely functionalized 3-hydroxy-P-lactams . 

Racker et al. have developed an interesting new combinatorial method for the synthesis of [l,4]oxazepin-7-ones (eg 139, R = Ph) from aldehydes and a-amino alcohols with the Baylis-Hillman reaction being a key step . 

A titanium(iv) chloride mediated Baylis-Hillman-type or aldol reaction between a-ketoesters and cyclohex-2-enones has been studied (Equation (13)).77 The steric effect of the R2 substituent is crucial for the reaction pathway since the aldol reaction only proceeds with the unsubstituted cyclohexenone (aldol adduct 71 with R2 = H to a small extent the Baylis-Hillman reaction occurs), whereas with the substituted substrate (R2 = Me) gives exclusively the Baylis-Hillman adduct 72. 

The synthesis shown in Fig. 40 provided access to heptoses,55 but according to our definition, this is not a higher sugar synthesis. However, the approach to such derivative was based on the Baylis-Hillman reaction of acyclic sugar-derived aldehydes, a reaction not commonly applied in sugar chemistry and worth to mention in this review. 

A fundamentally different approach to the synthesis of 3-pyrrolines is evidenced in the annulation in Eq. 13.50 [58]. Ethyl 2,3-butadienoate 150 reacts with N-sulfony-limine 151 in the presence of triphenylphosphine under very mild conditions to give JV-protected 3-pyrroline 152 in 90% yield. The mechanism that has been postulated is related to that of the Baylis-Hillman reaction. Michael addition of triphenylphosphine to the allenyl ester generates a zwitterion that combines with the imine to give 153 in a non-concerted process. This is followed by ring closure, proton exchange and expulsion of triphenylphosphine to give 152. This annulation is successful only for aromatic or cinnamyl imines [59]. 

The Baylis-Hillman reaction (Scheme 3) of ethyl vinyl ketone with electron-deficient aromatic aldehydes (e.g. where R = 0-NO2C6H4), in MeCN or EtCN solution, has been found to proceed enantioselectively in presence of catalytic base (32) derived from proline. The Michael adduct formed between the catalyst and the vinyl... 

The promoters of the so-called chalcogenide Morita-Baylis-Hillman reaction are Kataoka and co-workers who employed sulfide and TiCl for dual Lewis acid-base activation. Later, in 1996 the ability of the combination of sulfide/TBDMSOTf to promote the reaction was reported [110], Asymmetric version of the Baylis-Hillman reaction has been achieved by using chiral sulfide in place of SMe. The best ee was 94% in combination with a high yield of 88% in 5 h (Scheme 39) [ 111 ]. 

Unfortunately, starting from the preformed imine and acrylate under conditions optimized for the Baylis-Hillman reaction, the authors could not reproduce the results from the Baylis-Hillman trials they obtained only conversions up to 46% and yields of up to 30% (Scheme 39) [89]. 

Because many of them are nearly inert, ionic liquids have been used to stabilize highly polar or ionic transition states. Ionic liquids provide favorable media for the formation and stabilization of intermediates in reactions that proceed through charged intermediates. An example is the Baylis-Hillman reaction catalyzed by 1,4-diazabicyclo (222). octane (DABCO) (Scheme 8) (162). 

In the proposed mechanism (Scheme 9), the rate-determining step is the reaction between aldehyde and enolate. In the absence of a solvent, a major issue with this reaction is the typical low rate and the need for a high concentration of catalyst (usually DABCO). It was reported recently that, under basic conditions, the ionic liquid [BDMIM][PF6] is inert and that the Baylis Hillman reaction in [BDMIMjPFg proceeds smoothly with better yields than in [BMIMjPFg (163). 

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