DABCO Morita-Baylis-Hillman reaction

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... 

Significant rate enhancement of the Morita-Baylis-Hillman reaction through solid-state milling has been noted by Mack et al. (Scheme 2.44). [39], In such conditions, Baylis-HiUman products 130 were obtained in up to >98% yield in as little as 0.5 h by solvent-free reaction of p-nitrobenzaldehyde 129 and methyl acrylate 128. Various bases were tested and l,4-diazabicyclo[2.2.2]octane (DABCO) showed the best performance (Table 2.41). Other p-substimted aromatic aldehydes reacted with methyl acrylate much slower, within 9 5 h and lower yields (28-97%) were obtained. This represents one of the fastest methods of Bayhs-Hilhnan reactions under neat conditions. One of the main drawbacks of this reaction carried out in classical conditions is its slow rate, which has been shown typically to take days to weeks to produce adequate product yields. 

A remarkable rate acceleration of the Morita-Baylis-Hillman reaction of aldehyde ArCHO and activated alkene CH2=CH(EWG), catalysed by 1,4-diazabicyclo[2.2.2]octane (DABCO) (20mol%), has been reported for the solvent-free neat conditions. ... 

In the catalytic asymmetric aza-Morita-Baylis-HiUman reaction using unactivated methyl acrylate, the combined use of a La(0- Pr)3/(5, 5 )-TMS-linked-BINOL complex with a catalytic amount of l,4-diazabicyclo[2.2.2]octane (DABCO) promoted the aza-Morita-Baylis-Hillman reaction of a broad range of A-diphenylphosphinoyl imines." ... 

The Morita-Baylis Hillman reaction of cyclic enones with aromatic aldehydes was also studied by Shi and Liu by involving bis-thiourea organocata-lysts derived from BINAM. The reactions were performed in the presence of DABCO and afforded the desired products in good yields and enantioselec-tivities of up to 88% ee, as shown in Scheme 2.57. 

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. 

In 2004, Krishna and coworkers [59] reported that optically active a-methylene-y- and S-lactones can be obtained via intramolecular asymmetric Morita-Baylis-Hillman reaction starting from enantiomerically pure starting materials (Scheme 4.28). Diastereoselective cyclizations of chiral acrylates 103 and 105 were realized using DABCO as nucleophilic promoter. P,y-Disubstituted-a-methylene-y-lactone 104 and bicyclic a-methylene-8-lactone 106 with hydroxyl substituent in the 3-position were readily accessed following such strategy. 

Morita-Baylis-Hillman reaction The Morita-Baylis-Hillman (MBH) reaction of aldehydes RCH=0 with the methylene acceptor CH2=CHC02Me, catalysed by DABCO in ionic liquids possessing [EtS04] anion, has been found to exhibit second-order kinetics in aldehyde and first order in acrylate and DABCO. This behaviour is in line with the kinetics reported for DMSO and other aprotic polar solvents but differs from the general observation of the first order in aldehyde, acrylate, and DABCO in other organic solvents. ... 

Scheme 7.27 Fluorous DABCO-catalyzed Morita-Baylis-Hillman reaction.

The Morita-Baylis-Hillman (MBH) reaction is an important 100% atom economic transformation that allows the formation in one step of a flexible allylic alcohol motif. Efforts in this field have been directed recently to the solution of two problems to enhance the generally sluggish reaction rate and to achieve asymmetric catalytic versions. Scheme 1.15 gives the catalytic cycle of the MBH reaction. The catalyst is a highly nucleophilic tertiary amine, generally DABCO, or a tertiary phosphine, which adds to the oc,P-unsaturated electrophile in a 1,4 fashion to deliver an enolate that, in turn, adds to the aldehyde. A critical step is the proton transfer from the enolizable position to the oxygen atom this process is catalysed by an alcohol that plays the role of a proton shuttle between the two positions. Water has also been reported to strongly speed up the reaction at a well-defined concentration. Moreover, the... 

Renewed interest in the Morita-Baylis-Hillman (MBH) reaction comes from recent activation processes. Traditional tertiary amines such as DABCO serve as basic catalysts (Scheme 10.17). However, the reaction is usually sluggish unless powerful activation is used. 

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]. 

Subsequently, multicomponent reactions were less explored. In 1998, Richter and Jung reported a three-component reaction of a polymer-bound acrylate, aldehydes and sulfonamides in the presence of DABCO as catalyst in dioxane. After cleavage from the polymer support, the desired Morita-Baylis-Hillman adducts 214 were obtained in good yields with moderate to high purities (Scheme 1.81). 

A phosphine sulfonamide derived from L-threonine promotes aza-Morita-Baylis-Hillman (aza-MBH) reactions of sulfinylimines in up to 96% yield and 97% ee. A review describes the synthesis of chiral amines under mild conditions via catalytic asymmetric aza-MBH reactions. Proline/DABCO (l,4-diazabicyclo[2.2.2]octane) co-catalysis of enantioselective aza-MBH reactions gives good to high yields and up to 99%... 

The Morita-Baylis-Hillman (MBH) reaction can be broadly defined as a coupling reaction between an alkene activated by an electron-vfithdrawing group and an electrophile that occurs under Lewis base catalysis, l,4-diazabicyclo[2.2.2]octane (DABCO) normally being used as the base (Scheme 3.1) [3]. 

We then investigated the CDC reaction between a-sp C-H bonds of nitrogen in THIQs and sp C-H bonds of electron-deficient alkenes. The reaction generated the Morita-Baylis-Hillman (MBH) reaction product by using l,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst (Scheme 1.11). Another common MBH catalyst, triphenylphosphine, was found to be nearly ineffective due to the generation of triphenylphosphine oxide during the reaction. 

Carbon-carbon bond forming reactions constitute die core of organic synthesis, and novel, efficient methods are always desirable. One such reaction that has attracted much attention in recent days is the Morita-Baylis-Hillman (MBH) reaction the reaction of activated olefins with reactive carbonyls or imines in the presence of a catalytic amount of trialkyl(aryl)phosphine or amine (i-i). Of all the amines tested, 1,4-diazabicyclo[2.2.2]octane (Dabco) has been found to be superior (Scheme 1). This reaction, which provides multifunctional molecules has been accommodated in certain undergraduate curriculum (4), and does not demand any sophisticated techniques or instrumentation. 

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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