Baylis-Hillman reaction product

Conjugate additions. Cuprate addition to ynoate esters and trapping with aldehydes (in the presence of EtjAlCl) provide special analogs of Baylis-Hillman reaction products. Trapping with phosphonoacetatic esters is another synthetically valuable variation. Silyl ketene acetals derived from 1,6-addition to allyl alk-4-yn-2-enoates undergo Claisen... 

Heck reaction. An intramolecular version is exploited in closing the five-membered ring to complete the tetracyclic system of mappicine. A new synthesis of P-ketoesters is via the Heck reaction of aryl halides with the Baylis-Hillman reaction products. Additives have important influences on the products derived from aryl halides and 2,3-dihydrofuran ... 

Propose a mechanism for the following formation of the aza Morita Baylis Hillman reaction product that is obtained from an a hydroxypropargylsilanc (1) and the N tert butanesulfinyl imine. Provide the structure of intermediate A obtained upon slow addition of n BuLi to ( ) 1. 

Baylis-Hillman reaction products are obtained in an unconventional manner from a-silylpropargyl alcohols and aldehydes, using l,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene as catalyst. ... 

Benzpyloxymethyl-2-alkenoic esters. These esters are formed when the Baylis-Hillman reaction products are subjected to the reaction of Pl P-DEAD and a carboxylic acid. An Sj 2 pathway is followed. The addition of EtjN is beneficial, because it undergoes quatemization. Thus, the subsequent displacement by the carboxylate ion affords much more rearranged (S 2 ) products. 

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. 

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 ... 

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. 

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. 

PDMS thimble contained in glass vial. The substrate, an acetal, is within the PD MS thimble and undergoes an acid-catalyzed transformation into an aldehyde. The aldehyde then diffuses to the exterior and undergoes the Baylis—Hillman reaction catalyzed by DMAP to give the product, (b) Various acid and base... 

A Baylis-Hillman type product has been obtained through a ring-opening reaction of an epoxide with an allenoate <06OL2771>. The reaction of MgL, with ethyl propiolate provides the iodo allenoate 32. This nucleophile reacts with an aryl epoxide to provide the homoallylic alcohol 33. The Z iodide is the major product formed. 

The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true Morita-Baylis-Hillman reaction of an epoxide has recently been reported <06CC2977>. Treatment of enone 34 with Me3P provides a good yield of the epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. 

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],... 

When methylene bisphosphonate (169) is reacted in a Horner reaction with an aromatic aldehyde, the alkenyl phosphonate 170 is produced (Scheme 5.25). By metalation with LDA in THF, this is converted to the vinyllithium intermediate 171 that, with the ketone 172, affords a Baylis-Hillman reaction-type product, 173 on base treatment, this is converted to the arylallene 174 [67]. 

An interesting alternative intramolecular cyclisation was discovered by Jprgensen and co-workers [187]. Although not strictly exploiting an enamine intermediate, the transformation represents a secondary amine catalysed Morita-Baylis-Hillman reaction leading to a series of highly functionalised cyclohexene products. Reaction of the Nazarov reagent 137 with a,P-unsaturated aldehydes in the presence of the diarylprolinol ether 30 led to the cyclohexene products 138 (49-68% yield 86-96% ee) via a tandem Michael/Morita-Baylis-Hillman reaction (Scheme 54). 

The conversion rate in aza-Baylis-Hillman reactions is generally low, which leads to extended reaction times [87]. Heating is normally used to increase the reaction speed however, it also promotes the formation of side products. Alternatively, microwave heating was successfully used as a way of promoting the reaction [92]. However, microwaves-promoted reactions are not easy to scale-up. Guided by this, the Stevens research group [89, 93] used the commercial CYTOS College System [18] to perform these reactions on a microscale in a continuous manner in order to improve the reaction rates and make it industrially more applicable. 

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... 

There has been a continuing effort to make the Baylis-Hillman reaction a catalytic asymmetric process. Scott Schnauss of Boston University recently reported (J. Am. Chem. Soc. 125 12094, 2003) an elegant solution to this problem, based on the use of Binol-derived Bronsted acids as catalysts. The product hydroxy enones such as 6 are interesting in themselves, and also as substrates for further transformation, for instance by Claisen rearrangement. 

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 study of the effect of the Michael acceptor configuration on the efficiency of intramolecular Morita-Baylis-Hillman reactions has been performed. Enones containing a pendant aldehyde moiety attached at the -position of the alkene group were employed as substrates and the reactions were catalysed by a phosphine. In all cases examined, with Ph3P as the catalyst, cyclization of (Z)-alkene (117) gave 2.5-8.5 times higher yield than with the E-isomer (115) under identical reaction conditions, both affording the same product (116). Steric effects are believed to be the source of this difference in reactivity.172... 

The aza-Baylis-Hillman reaction of 4-X-C6H4CH=NTs with CH2=CHCOMe, catalysed by PI13P in the newly designed chiral ionic liquid (121), derived from l-(—)-malic acid, gave products with up to 84% ee. This example represents the first highly enantioselective asymmetric reaction in which a chiral medium is the sole source of chirality.176... 

One potential problem in the reactions of stabilized allylic or propargylic carb-anions is the dimerization of the starting material if the carbanions are not formed stoichiometrically. Alkenes substituted with electron-withdrawing groups are good Michael acceptors, to which nucleophiles will undergo conjugate addition. For instance, the Baylis-Hillman reaction of allyl cyanide with benzaldehyde requires careful optimization of the reaction conditions to avoid dimerization of the nitrile (Scheme 5.12). This problem is related to a common side reaction of Michael additions reaction of the product with the Michael acceptor (Scheme 10.21). 

Studies on catalytic asymmetric aza-Baylis-Hillman reaction has shown that the reaction involves rate-limiting proton transfer in the absence of added protic species, but exhibits no autocatalysis.41 Brpnsted acidic additives lead to substantial rate enhancements through acceleration of the elimination step. Furthermore, it has been found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the aza-Baylis-Hillman product by proton exchange at the stereogenic centre. 

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... 

Product formation and yields in the Baylis-Hillman reaction also depend on a balance between the reactivities of the carbonyl and olefin partners as was shown, for example, for reactions of fluorine-containing carbonyl compounds [13]. 

Shi and coworkers have reported that the rate and product distribution of Baylis-Hillman reactions of aldehydes with a,/ -unsaturated ketones can be drastically affected by the reaction temperature and by the presence of Lewis bases [18]. When the reaction was carried out at -78 °C using catalytic amounts of quaternary ammonium salts as Lewis bases, in the presence of titanium] IV) chloride, chlorinated syw-aldol adducts were obtained as the major products. Quaternary ammonium bromides and iodides showed higher catalytic activity than... 

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... 

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. 

Warren and coworkers have reported an interesting synthesis of nonracemic allenes by reaction of vinylphosphine oxides with aldehydes in the presence of chiral lithium [(R)-l-phenylethyl](benzyl)amide to give hydroxyvinylphosphine oxides in 33-87% yields (0-51% ee) [38]. These products underwent a Horner-Wittig elimination reaction to produce nonracemic allenes. A mechanism similar to the Baylis-Hillman reaction was suggested. 

The asymmetric domino reaction between 2-mercaptobenzaldehyde and a,f)-unsaturated aldehydes proceeds with excellent chemo- and enantio-selectivities to afford 2-substituted 3-formyl-2//-l bcnzothiopyrans, products of a formal Baylis-Hillman reaction, when the. 9-proline derived catalyst 407 is employed (Scheme 123) <2006TL8547>. 

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