Baylis-Hillman reaction amine catalysts

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. ... 

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

In this particular system, 4-nitrobenzaldehyde dimethyl acetal is deprotected by the acid catalyst, followed by the addition of methyl vinyl ketone (MVK) in an amine-catalyzed Baylis-Hillman reaction to give the product (Scheme 5.14). A yield of 65% for the final product was observed when the catalysts described in Scheme 5.13 were used, compared with no observed yield for the reaction with their soluble analogs. 

The aldehyde can be replaced by an imine and the reaction is then called the aza-Baylis-Hillman reaction [87, 88]. (3-Amino-a-methylene structures obtained in this way could further be converted to a range of biologically important molecules, such as p-amino acids [89]. First reaction of this kind was published in 1984 [90]. Tosylimines and ethylacrylate reacted in the presence of DABCO as catalyst to give p-aminoesters. First three-component aza-Baylis-Hillman reaction was published in 1989 by Bertenshaw and Kahn [91], with imine formation in situ from an aldehyde and an amine. In the presence of triphenylphosphine as catalyst, the reaction with methylacrylate led to the formation of the p-amino-ot-methylene esters and ketones in good yields (Scheme 38). 

Baylis-Hillman reactions, the protonated amine was the governing factor in determining catalyst efficiency, thus making quinuclidine itself a better catalyst than 3-heteroatom substituted analogs, which are of reduced basicity/nucleophilic-ity and consequently give lower reaction rates. 

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... 

Baylis-Hillman reactions of benzaldehyde and its 2-nitro derivative with o /3-unsaturated esters and nitriles have been carried out in water at pH 1 (T = 0 or 25 °C), with tertiary amine catalysts.169... 

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 rate and the conversion of the Baylis-Hillman-reaction was significantly improved when nucleophilic non-hindered bases, such as diaza[2.2.2]bicyclooctane (DABCO, 6), rather than simple tertiary amines were used. Further improvements were observed when 3-quinuclidinole (3-QDL, 7) was employed, due to stabilization of the zwitterionic intermediate 2 by formation of intramolecular hydrogen bonds [14a-c]. Similar effects were observed by the addition of methanol [14d] or acetic acid [14e] to the reaction mixture (formation of intermolecular hydrogen bonds) or by the presence of a hydroxy group in the acrylate [14f ]. The rate of the reaction was decreased by the presence of substituents in the a-position of tertiary amines. This was explained by the decrease of the rate of the addition of the catalyst onto the acrylate [15]. 

A substantial acceleration of the Baylis-Hillman reaction has been observed when the reaction was conducted in water [19, 20]. Several different amine catalysts were tested by Aggarwal and coworkers, and as with reactions conducted in the absence of solvent, 3-hydroxyquinudidine was found to be the optimum catalyst in terms of rate [19]. The reaction has been extended to other aldehyde electrophiles including pivaldehyde. Further studies on the use of polar solvents revealed that formamide also provided significant acceleration. 

Selenium-containing six-membered ring heterocycles have proved to be useful catalysts in a variety of transformations. The Baylis-Hillman reaction involves the reaction of alkenes containing electron-withdrawing groups such as a,/3-unsaturated carbonyl compounds with aldehydes leading to carbon-carbon bond formation (Equation 79). The reaction is promoted by tertiary amines such as l,4-diazabicyclo[2.2.2]octane (DABCO), or tertiary phosphines and Lewis acids. Unfortunately, the Baylis-Hillman reaction is severely limited because it proceeds only very slowly <1998CC197>. Much research has been carried out in attempts to increase the rate of this reaction. 

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. 

The currently accepted mechanism of the Baylis-Hillman reaction involves a Michael addition of the catalyst (tertiary amine) at the (3-position of the activated alkene to form a zwitterionic enolate. This enolate reacts with the aldehyde to give another zwitterion that is deprotonated, and the catalyst is released. Proton transfer affords the final product. 

Balan, D., Adolfsson, H. Chiral quinuclidine-based amine catalysts for the asymmetric one-pot, three-component aza-Baylis-Hillman reaction. Tetrahedron Lett, 2003, 44, 2521-2524. 

The polymer-supported 4-(A -methylamino)pyridine (Figure 3.4), prepared by reaction of 4-chloromethylstyrene and 4-(methylamino)pyridine sodium salt and successive copolymerization with styrene and divinyl benzene,was utilized as reusable catalyst for promoting the Baylis-Hillman reaction usually this kind of reaction uses stoichiometric or overstoichiometric amounts of an organic amine as a base catalyst. 

The Baylis-Hillman (also called Morita-Baylis-Hillman) (MBH) reaction (see Sect. 10.2.4 and Scheme 10.17) is the base-catalyzed addition of keto compounds to acrylic derivatives. The catalyst is a cyclic tertiary amine such as 1,4-diazabicyclo[2.2.2]octane (DABCO). Due to the generally poor yields observed, the reaction has not received sufficient attention despite the great synthetic value of the polyfunctional adducts. Among the various methods proposed to activate the reaction, pressure 107] and hydrophobic effects [70] have been used. Table 10.31 presents the results obtained in some Baylis-Hillman reactions carried out under pressure in aqueous solution [108]. 

Enolates, generated by Michael addition reactions of a,p-unsaturated esters or ketones, can add to aldehydes. If the Michael addition is carried out with a tertiary amine (or phosphine) then this is referred to as the Baylis-Hillman reaction. Typically, an amine such as l,4-diazabicyclo[2.2.2]octane (DABCO) is used. After the aldol reaction, the tertiary amine is eliminated and it can therefore be used as a catalyst (1.61). The reaction is somewhat slow (requiring several days), but rates may be enhanced with other amines such as quinuclidine or quinidine derivatives, the latter effecting asymmetric reaction with high levels of selectivity. ... 

Baylis-Hillman reaction in synthetic chemistry (particularly, cyclic amines as catalysts) 07CSR1581. 

Amine-catalyzed Baylis-Hillman reaction (proline, l-azabicyclo[2.2.2] octane, imidazole, etc. as catalysts) 05CJO763. 

The coupling reaction between an electron-deficient alkene and an aldehyde (Baylis-Hillman reaction) usually requires a cata-lyst/catalytic system (typically, a tertiary amine and a Lewis acid) to be successful. The base catalyst is not necessary when pyridine-2-carboxaldehyde is employed as electrophile it is enough with the activation effected by stoichiometric amounts of TMSOTf for the reaction to proceed to give indolizidine derivatives (eq 71). ... 

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. ... 

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). 

Another class of reaction for which chiral tertiary amines are privileged catalysts is the Morita-Baylis-Hillman type (477, 478). One of the first applications of Cinchona alkaloids to mediate an asymmetric Morita-Baylis-Hillman reaction in a natural product synthesis was reported by Hatakeyama et al. in 2001 (479). Using a stoichiometric amount of (3-isocupreidine (568), a stereoselective addition of hexafluoroisopropyl acrylate (569) to aldehyde 570 could be carried out in good yield and with excellent selectivity (99% ee) (Scheme 119). The chiral p-hydroxy ester 571 was converted further into the epoxide 572, a known intermediate in the synthesis of epopromycin B (573). Epopromycin B (573) is a plant cell wall... 

As an extension of this work, the same authors have used polystyrene-supported proline as a recyclable catalyst in the Morita-Baylis-Hillman reaction of a range of aryl aldehydes with methyl or ethyl vinyl ketone. These reactions were performed in the presence of imidazole and provided a series of Morita-Baylis-Hillman adducts in moderate to high yields (17 88%) combined with high enantioselectivities of up to 95% ee (Scheme 2.55). This study represented the first example of supported proline as heterogeneous catalyst for the Morita-Baylis-Hillman reaction. In addition, Zhou et al. reported that these reactions could be eatalysed by combinations of L-proline with chiral tertiary amines derived from various readily available chiral sources, such as L-proline or (5)-a-phenylethylamine. In these conditions, the Morita-Baylis-Hillman adducts were obtained in reasonable chemical yields (34-97%) and low to good enantioselectivities (12 83% ee). In this study, it was demonstrated that the proline stereochemistry was the sole factor to determine the eonfiguration of the newly formed chiral centre. 

Amino-a-methylene carbonyl compounds have been prepared in up to 92% ee via an aza-Morita-Baylis-Hillman reaction. A-Tosyl imines of, y-unsaturated a-ketoesters have been reacted with acrolein in the presence of two catalysts / -isocupridine (a chiral quinolol containing a DABCO moiety) and a bifunctional BINOL (or a 3 amine-thiourea). NMR and MS evidence supports a self-assembly of the catalysts, giving a multi-functional supramolecular catalyst. 

Baylis-Hillman reaction of an aldehyde with an a.y -unsaturated carbonyl compound is catalysed by l,4-diazabicyclo[2.2.2]octane (DABCO) a zwitterionic intermediate (60) is proposed. Lithium perchlorate is found to accelerate the reaction further (in diethyl ether solvent), presumably through further stabilization of such a species. The effect is not seen with most other metal salts, presumably because they cannot act as efficient, independent co-catalysts in the presence of a tertiary amine. 

A highly enantioselective Baylis-Hillman reaction based on the combined use of an activated alkene (23) and a chiral amine catalyst (QDA) derived from cincho-nane has been developed. The reaction permits the conversion of a wide variety of aldehydes to the corresponding a-methylene-jS-hydroxy esters (28) with high ee in reasonable yields. 

Conditions for a highly enantioselective Baylis-Hillman reaction (142) + (143) (144) have been developed (Scheme 20). The new protocol relies on the use of 1,1,1,3,3,3-hexafluoroisopropyl acrylate (144) as an activated alkene and (3R,8R,9S)-10,ll-dihydro-3,9-epoxy-6 -hydroxycinchonane (145) as a chiral amine catalyst. The highest enantioselectivity (99% ee) was obtained for R = cyclohexyl. A mechanism has been proposed that highlights an important synergism of the tertiary nitrogen and the phenolic OH of the alkaloid (143) + (145) —> (146) + (147). 9 However, the reviewer feels that the proposed mechanism would be disfavoured by the entropy factor. 

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