DABCO Baylis-Hillman reaction

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. ... 

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... 

It should be noted that Baylis-Hillman reaction of Garner s aldehyde with methyl acrylate and DABCO results in racemization of the stereocenter of the amino aldehyde [61]. In the case of substrate 56 such racemization is seriously hampered due to the large inversion barrier in three-membered ring compounds [62]. 

It should be noted that catalytic amounts of feA-arylureas and bis-arylthioureas greatly accelerated the DABCO-promoted Baylis-Hillman reaction of aromatic aldehydes with methyl acrylate in the absence of solvent. These robust organocatalysts were better mole-per-mole promoters of the reaction than either methanol or water and they were recovered in higher yields.106... 

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],... 

Phosphonium salts have also been used as co-catalysts in the DABCO catalyzed Baylis-Hillman reaction of methyl acrylate with benzaldehyde [122]. Good results were obtained with triethyl-n-butylphosphonium tosylate with up to quantitative yields in some cases. The authors proposed that the phosphonium salt is rather stabilizing the intermediate 50, shown in Scheme 48, and increasing therefore its concentration rather than activating the benzaldehyde. 

Ionic liquids have been also explored in the Baylis-Hillman reaction [204-206]. The application of the enantiopure ionic liquid 73 in the Baylis-Hilhnan reaction by Vo-Thanh [207] resulted in an enantiomeric excess of up to 44% with 1 equiv. of the Lewis base catalyst DABCO (Scheme 81). It was shown that it was essential to have a hydroxy group incorporated in the ionic liquid in order to obtain significant ee. 

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). 

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). 

Substituted allyl alcohols can be prepared on insoluble supports under mild conditions using the Baylis-Hillman reaction (Figure 7.2). In this reaction, an acrylate is treated with a nucleophilic tertiary amine (typically DABCO) or a phosphine in the presence of an aldehyde. Reversible Michael addition of the amine to the acrylate leads to an ester enolate, which then reacts with the aldehyde. The resulting allyl alcohols are valuable intermediates for the preparation of substituted carboxylic acids [43,44],... 

The continuous and batch microwave reactors have been particularly useful for heating reactions in which thermally labile products are formed. For example, alkyl 2-(hydroxymethyl)acrylates have considerable potential as functionalised monomers and synthons128. Published syntheses at ambient temperature, however, required several days and were not conducive to scale-up129-133. The microwave procedure involved a modified Baylis-Hillman reaction, in which the parent acrylate derivative was reacted with formalin in the presence of 1,4-diazabicyclo [2.2.2] octane (DABCO). Preparations from starting acrylates, including methyl, ethyl and n-butyl esters, were easily achieved within minutes with multiple passes through the CMR, at ca. 160-180°C (Scheme 9.16). Rapid cooling was required to limit hydrolysis, dimerisation and polymerisation. Yields... 

The reaction between an unsaturated ester and an aldehyde catalysed by DABCO (the Baylis-Hillman reaction) is catalysed by lanthanides and Group III inflates, particularly La and Sm, and additional acceleration can be obtained by addition of diol ligands.188... 

The formation of rings with more than seven atoms has unfavorable rates because the addition step is often too slow to allow it to compete successfully with other pathways open to the radical intermediate. In stannane based chemistry for example, premature hydrogen abstraction from the organotin hydride is difficult to avoid. However, Baylis-Hillman adducts 111 derived from enantiopure 1-alkenyl (or alkynyl)-4-azetidinone-2-carbaldehydes are used for the stereoselective and divergent preparation of highly functionalized bicycles 112 and 113 fused to medium-sized heterocycles (Scheme 38) [80, 81]. The Baylis-Hillman reaction using nonracemic protected a-amino aldehydes has been attempted with limited success due to partial racemization of the chiral aldehyde by DABCO after... 

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

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 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]. 

During the course of the Baylis-Hillman-reaction two stereocenters are formed, one of which remains in the Baylis-Hillman-product. An obvious concept for the development of an asymmetric version of the reaction represents the use of an enantiomerically pure acrylic acid derivative. The use of enantiomerically pure menthyl acrylates resulted, but only in certain cases, to respectable diastereomeric excesses [21]. A significant improvement was reported in 1997 by Leahy and coworkers who used the Oppolzer-sultame as a chiral auxiliary in DABCO-catalyzed Baylis-Hillman-reactions (Scheme 2) [22]. In this reaction, the... 

Asymmetric Baylis-Hillman reactions using sugar acrylates have been reported to proceed with moderate diastereoselectivity (5-40% ee) [23]. The reaction of camphor-based chiral acryloylhydrazides with aldehydes in the presence of DABCO afforded /1-hydroxy-a-methylene carbonyl derivatives in 68-92% yield with high diastereoselectivity (up to 98% de) [24]. Both diastereomers could be selectively obtained simply by changing the solvent. 

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 DABCO-promoted Baylis-Hillman reaction was run continuously using the CYTOS College System (CPC Systems GmbH) with yields comparable to those of the batch reaction and with a significant reduction in reaction time (Scheme 4.10) [14]. Coupled with the stopped-flow technique, an almost complete conversion was achieved. 

A disadvantage of the Baylis-Hillman reaction is Its rate typically, several days reaction time are required. Pressure helps speed the reaction up, but as a catalyst DABCO is about the best. It is nucleophilic, because of the tied back alkyl groups, but importantly it is a good leaving group because it has a... 

Baylis-Hillman Reaction. Intramolecular cyclization of MeC0(CH2)2CH=CHC02Et using (-P)-CAMP produced the cy-clopentene in 40% isolated yield. A 3 1 equilibrium mixture which favored the product cyclopentene was formed after 10 days at 25 °C. CAMP was found to be superior to other phosphines, such as PBU3. DABCO and other nitrogen bases were ineffective for the cyclization reaction. However, the enantioselectivity of the product using CAMP was only 14%. 

One of the most important uses of DABCO is in the Baylis-Hillman reaction, discovered in 1972 by two chemists at the Celanese Corporation in New York. Their reaction is a modification of the aldol reaction (Chapter 27), except that, instead of the enolate being formed by deprotonation, it is formed by conjugate addition. You have seen the enolate products of conjugate addition being trapped by alkylating agents in Chapter 26, but in the Baylis-Hillman reaction, the electrophile is an aldehyde and is present right from the start of the reaction, which is done just by... 

The Baylis-Hillman reaction has become a very powerful carbon-carbon bond forming reaction in the past 20 years. A typical reaction involves an activated olefin (i.e., an acrylate) and an aldehyde in the presence of a tertiary amine such as diazobicyclo-[2.2.2]octane (DABCO) to form an a-meihylhydroxyacrylale. A host of activated olefins have been utilized including acrylates, acroleins, a, 3-unsaturated ketones, vinylsulfones, vinylphosphonates, vinyl nitriles, etc. The Baylis-Hillman has been successfully applied inter- and intramolecularly. In addition, there are numerous examples of asymmetric Baylis-Hilhnan reactions. Reviews (a) Ciganek, E. Org. React. 1997, 51, 201-478. (b) Basavaiah, D. Rao, P. D. Hyma, R. S. Tetrahedron 1996, 52, 8001-8062. (c) Fort, Y. Berthe, M. C. Caubere, P. Tetrahedron 1992, 48, 6371-6384. 

In this subsection, we describe a couple of examples taken from the recent literature, in which the Baylis-Hillman reaction has been employed for the construction of new carbon-carbon bonds. The Baylis-Hillman reaction proceeds in a catalytic cycle propagated by a nucleophilic catalyst (584). The nucleophilic catalyst initiates the cycle by Michael addition to a double bond bearing an EWG (586 or 590). The carbon a to the EWG is acidic and may react with an electrophile. Finally, the nucleophilic catalyst is eliminated, completing the cycle (Scheme 122). The most frequently used catalysts are quinuclidine, DABCO, phosphines, thiopheno-lates, and selenophenolates. The reaction rate of a catalytic Baylis-Hillman reaction approaches a maximum at a certain temperature and declines upon further heating, as the equilibrium concentration of (587) becomes very small. In the first example, the electrophilic component of the reaction was immobilized on a solid phase and the nucleophile was in solution, while in the other example the situation was reversed (Scheme 122). 

Baylis-Hillman reaction The aforementioned resin was treated with DMSO (700 (b) followed by DABCO (3 equiv.), and the mixture was shaken for 30 min. A solution of a 3-substituted phenyl-5-isoxazolecarboxaldehyde... 

We chose 2-chlorotrityl chloride resin for the attachment of acrylic acid, because in solution-phase chemistry the best results have been obtained by using aryl acrylates or (erf-butyl acrylates [21], In addition to DABCO (1,4-diazabicyclo [2.2.2]octane) - the most common tertiary cyclic amine for this type of reaction - we also used the more reactive 3-quinuclidinol (3-hydroxy-quinuclidine, 3-HQN) for the Baylis-Hillman reaction with aldehydes. We used 26 different aldehydes and obtained good to excellent purities, as determined by analytical HPLC. 

The three-component Baylis-Hillman reaction was also performed on 2-chlorotrityl chloride resin by treating polymer-bound acrylic acid with aldehydes and sulfonamides in dioxane at 70 °C for 16 h under DABCO catalysis (Fig. 6.4). Both scaffolds, 3-hydroxy-2-methylidene propionic acids as well as 2-methylidene-3-aminoarylsulfonyl-propionic acids, are precursors for the synthesis of MCSLs. 

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