Acrylates 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. 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

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]. 

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... 

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... 

The 1,2-benzothiazepine 1,1-dioxides 126 were prepared in fair yields (e.g. 126, R = H, Ar = p-ClC6H4, 52%) by a Heck coupling on the precursors 125, which were obtained in turn from an aza Baylis-Hillman reaction involving the appropriate sulfonamide, aldehyde, and methyl acrylate reactants <06TL8591>. 

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],... 

It is also possible to carry out a substrate-controlled reaction with aldehydes in an asymmetric way by starting with an acetylene bearing an optically active ester group, as shown in Eq. 9.8 [22]. The titanium—acetylene complexes derived from silyl propiolates having a camphor-derived auxiliary react with aldehydes with excellent diastereoselectivity. The reaction thus offers a convenient entry to optically active Baylis—Hillman-type allyl alcohols bearing a substituent (3 to the acrylate group, which have hitherto proved difficult to prepare by the Baylis—Hillman reaction itself. 

Also known as Morita-Baylis-Hillman reaction, and occasionally known as Rauhut-Currier reaction. It is a carbon—carbon bond-forming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be aldehydes, a-alkoxycarbonyl ketones, aldimines, and Michael acceptors. 

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. 

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]. 

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],... 

Sulfonamides can also be alkylated by support-bound electrophiles (Table 8.10). Polystyrene-bound allylic alcohols have been used to N-alkylate sulfonamides under the conditions of the Mitsunobu reaction. Oxidative iodosulfonylamidation of support-bound enol ethers (e.g. glycals Entry 3, Table 8.10) has been used to prepare /V-sulfonyl aminals. Jung and co-workers have reported an interesting variant of the Baylis-Hillman reaction, in which tosylamide and an aromatic aldehyde were condensed with polystyrene-bound acrylic acid to yield 2-(sulfonamidomethyl)acrylates (Entry 4, Table 8.10). 

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... 

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... 

Unfortunately, the applicability of the Baylis-Hillman-reaction is very often limited by low rates and conversions and low, highly substrate-depending yields. It is particularly important for the development of an efficient asymmetric version of the Baylis-Hillman-reaction that these problems are adequately addressed. The use of high pressure or of the microwave technique resulted in significant increase of the rate of the reaction, but only for a few substrates [11]. Increase of the reaction temperature above 20 °C resulted in polymerization of the sensitive acrylates. Recent work by Leahy and coworkers suggested that, counterintuitively, better yields and higher rates were observed at lower temperatures [12]. These results can be explained by the different rates of the formation of the diastereomeric base-acrylate-adducts (2A and 2B). 

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. 

Aggarwal and coworkers have studied the electrophilic behavior of enantiomerically pure N-p-toluenesulfinimines and N-tert-butanesulfinimines in the asymmetric Baylis-Hillman reaction with methyl acrylate with and without Lewis acids [26], In the presence of In(OTf)3 good yields and high diastereoselectivities have been achieved providing an effective route to /i-amino-a-methylene esters. 

Kundig and coworkers have reported the Baylis-Hillman-reaction of methyl acrylate and acrylonitrile with planar chiral arylaldimine tricarbonylchromium complexes, such as 19 (Scheme 4) [28]. These reactions proceeded by attack of the acrylate from the sterically less encumbered site of the metal complex and afforded the products 21 with very good diastereoselectivity. 

Phenylmenthyl acrylate has been used as a component in an asymmetric Baylis-Hillman reaction. Treatment of the acrylate with 1,4-Diazabicyclo[2.2.2]octane and benzaldehyde at 8 kbar of pressure delivers the a-(hydroxyalkyl)acrylate (eq 8). The product obtained has an 86% de. Menthyl acrylate is superior to the phenylmenthyl acrylate in this particular application. In a radical-mediated addition, phenylmenthyl acrylate gives rise to the a-pyridyl sulfide in 68% yield (eq 9). The final product is isolated with a 56% de. 

A clean, high-yielding asymmetric Baylis-Hillman reaction has been reported employing Oppolzer s sultam, it couples acrylates with a variety of aldehydes at 0 °C, with >99% ee in all cases described. Another new, practical variant of the reaction employs a phosphine catalyst, and here the temperature effect is critical the rate increases in either direction from room temperature, with a dramatic improvement observed at 0 °C. This imusual observation is explained in terms of a temperatiue-dependent equthbrium between efficient and inefficient intermediates. 

Substituted pyrazoline derivatives 744 were synthesized in high yields through the cycloaddition reactions of azides 742 with acrylates 743 under Baylis-Hillman reaction conditions (Equation 158) <2002SL513>. 

Shi, M., Chen, L.-H. Chiral phosphine Lewis base catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with methyl vinyl ketone and phenyl acrylate. Chem. Commun. 2003,1310-1311. 

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 order to access isoxazole-based potential antithrombotic agents [409], acrylic acid was loaded onto 2-chlorotrityl resin and then subjected to Baylis-Hillman reaction -with a variety of 3-substituted phenyl-5-isoxazolecarboxaldehydes (pre-... 

Methyl 3-hydroxy-4-methyl-2-methylenepentanoate3 was obtained by the means of a Baylis-Hillman reaction s as follows. To a 500-mL, one-necked, round-bottomed flask equipped with a magnetic stir bar were added 82.3 g (1.14 mol) of isobutyraldehyde, 109.2 g (1.27 mol) of methyl acrylate, 7.28 g (0.057 mol) of 3-hydroxyquinuclidine, and 20 mL of chloroform (to predissolve the catalyst). The mixture was stirred at room temperature for 48 hr and concentrated to give the hydroxy ester (50.0 g, 28%) as a pale yellow oil. The product can be distilled (bp 83-87°C at 3 torr) or used in Part A without further purification. In the latter event, yields are 10-20% lower. 

In the Morita-Baylis-Hillman reaction, enolate intermediates are formed by addition of a nucleophilic catalyst to an a, 3-unsaturated carbonyl compound. These intermediates can be trapped with a variety of electrophiles,402 including azodicarboxylic esters (Eq. 102).403 The reaction fails with ethyl acrylate. 

In the solid-phase Baylis-Hillman reaction developed in our group [19] resin-bound acrylic ester reacted with aldehydes to form 3-hydroxy-2-methylidene-propionic acids, or with aldehydes and sulfonamides in a three-component reaction to form 3-aminoaryl-2-methylidene sulfonylpropionic acids [20] (Fig. 6.4). 

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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