Intermediates zwitterionic, Baylis-Hillman

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. ... 

Chiral solvents rarely induce significant enantioselectivity, but ees up to 84% have been achieved in an aza-Baylis-Hillman reaction.161 Using an ionic liquid (IL), the anion of which is a dimalatoborate (54), it is suggested that the high enantioselectivity arises from strong ion-pair and hydrogen bond interactions with the zwitterionic intermediate of the reaction, i.e. IL-B- R3P+-CH2-CH=C(Me)-0 HO-IL. 

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... 

The stereoselective formation of carbon-carbon bonds is an important problem in organic chemistry. The Baylis-Hillman-reaction allows the direct preparation of oc-methylene-/ -hydroxycarbonyl compounds by base-catalyzed reaction of a,/ -unsaturated carbonyl compounds with aldehydes [1-3]. The first step of this reaction involves nucleophilic attack of the catalyst onto the Michael-acceptor 1 under formation of the zwitterionic intermediate 2. Subsequently, this intermediate reacts in the rate-determing step of the Baylis-Hillman-reaction with the aldehyde 3 under formation of the alcoholate 4 (Scheme 1). The product 5... 

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]. 

Hydroxybenzaldehydes react with alkyl vinyl ketones in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) to yield 3-acyl-277-chromenes (Scheme 19) <2000J(P 1)1331 >. The reaction proceeds via a Baylis-Hillman type pathway to form the zwitterionic intermediate 61 with subsequent cyclization and dehydration to afford 2-acyl-2H-chromenes (Scheme 19) <20030BC1133>. 

The kinetics of the aza-Morita-Baylis-Hillman reaction have been studied for a range of imine substrates in various solvents, using triphenylphosphine as catalyst, and p-nitrophenol as a Brpnsted acid co-catalyst. The effects of varying the phosphineiphenol catalyst ratio on the rate indicate interdependence between them. This and the solvent effects support reversible protonation of zwitterionic intermediates within the mechanism. ip-NMR and quantum calculations also support such a route. 

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. 

Apparently the hypothesis of a nucleophile-catalyzed reaction fits well with all the experimental data. However, there is still an additional question being the transformation of zwitterion 7 into the Baylis-Hillman product 3. Intermediate 7 may evolve to compound 3 either by an E2 or by an ElcB elimination process (Scheme 32.6). Based on experimental evidence, we only know that the fission of the vinylic a-proton should occur at some stage after the rate-determining step, because no deuterium KIE is detected. Only with this data in hand, it is impossible to decide between the E2 and ElcB elimination processes (Scheme 32.6). 

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. 

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