Baylis-Hillman reaction transformations

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. 

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... 

Porco s synthesis of ( )-kinamycin C (3) constituted the first reported route to any of the diazofluorene antitumor antibiotics. This synthesis invokes several powerful transformations, including a modified Baylis-Hillman reaction, a catalyst-controlled asymmetric nucleophilic epoxidation, and a regioselective epoxide opening to establish the D-ring of the kinamycins. The tetracyclic skeleton was constructed by an... 

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. 

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). 

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. 

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. 

Asymmetric organocatalytic Morita-Baylis-Hillman reactions offer synthetically viable alternatives to metal-complex-mediated reactions. The reaction is best mediated with a combination of nucleophilic tertiary amine/phosphine catalysts, and mild Bronsted acid co-catalysts usually, bifunctional chiral catalysts having both nucleophilic Lewis base and Bronsted acid site were seen to be the most efficient. Although many important factors governing the reactions were identified, our present understanding of the basic factors, and the control of reactivity and selectivity remains incomplete. Whilst substrate dependency is still considered to be an important issue, an increasing number of transformations are reaching the standards of current asymmetric reactions. 

Jauch achieved the short and elegant total synthesis of mniopetals during almost the same period in which our total syntheses were reported [36-41]. We briefly introduce Jauch s achievements on this subject. The key step of his synthesis was the IMDA reaction of 2-substituted butenolide 124 (Scheme 20), which was prepared by the diastereoselective PhSeLi-induced Baylis-Hillman reaction of 122 and Feringa s butenolide 123 [99]. The cycloadduct of this IMDA reaction 125 was transformed into kuehneromycin A and mniopetals E and F, respectively. 

Baylis-Hillman reaction in syntheses and transformations of heterocycles 03CRV811. 

Scheme 13.30 Transformations of aza MBH adduct. (Source l.T. Raheem, E.N. Jacobsen, Highly enantioselective aza Baylis Hillman reactions catalyzed by chiral thiourea derivatives. Adv. Synth. Catal. 2005, 347, 1701 1708. Wiley VCH Verlag GmbH. Reproduced with permission.)...

Polymer bound acrylic ester is reacted in a Baylis-Hillman reaction with aldehydes to form 3-hydroxy-2-methylidenepropionic acids or with aldehydes and sulfonamides in a three-component reaction to form 2-methylidene-3-[(arylsulfonyl)amino]propionic acids. In order to show the possibility of Michael additions, the synthesis of pyrazolones was chosen. The Michael addition was carried out with ethyl acetoacetate and BEMP as base to form the resin bound p-keto ester. This was then transformed into the hydrazone with phenylhydrazine hydrochloride in the presence of TMOF and DIPEA [28]. The polymer bound phenol was readily coupled to a variety of allyl halides by using the Pl- Bu to generate a reactive phenoxide [29]. 

Allyl cyanide on the other hand, Eq. (20), results in an allylic transposition affording only the Baylis-Hillman product. The Baylis-Hillman reaction has long been of interest. Generally, high pressure is required to induce such a reaction and an amine such as DABCO as well as lengthy reaction times (1-4 weeks) are usually required [131]. The transformation shown in Eq. (20) advantageously affords this product under very mild conditions and in very short reaction times compared with both older as well as more recent literature approaches. Furthermore, this reaction is successful with aromatic aldehydes that have generally led to unreliable results under typical Baylis-Hillman conditions. 

The Morita-Baylis-Hillman reaction is a powerful transformation in organic synthesis, consisting of the formation of a-methylene-p-hydroxy-carbonyl compounds by the addition of aldehydes to a,p-unsaturated carbonyl compounds, such as vinyl ketones, acrylonitriles or acrylic esters. For the... 

The ability of chiral binaphthoi (BINOL) derivatives as a Br0nsted acid catalyst to facilitate asymmetric transformations was demonstrated by Schaus by the development of the highly enantioselective Morita-Baylis-Hillman reaction of cyclohex-enone with aldehydes effectively catalyzed by (J )-octahydro-l,T-bi-2-naphthol derivatives, bearing either 3,5-bis(trifluoromethyl)phenyl (24a) or 3,5-xylyl (24b) groups at the 3,3 -positions, in combined use with triethylphosphine as a nucleophilic promoter (Scheme 7.43) [68]. 

Trost and coworkers have shown that Baylis-Hillman adducts can be efficiently derace-mized by Pd2dba3-CHCl3 catalyzed reaction of the corresponding carbonates 55 with phenols 56 in the presence of chiral C2-symmetric P,N-ligands (Scheme 11) [44], The strategy follows a dynamic kinetic asymmetric transformation process via jr-allyl palladium chemis-... 

Nucleophilic amines or alkyl phosphines can mediate the addition of electron-deficient alkenes to reactive carbonyls such as aldehydes or ketones. This transformation, which affords functionalized allylic alcohols, is generally termed the Morita-Baylis-Hillman (MBH) reaction (Scheme 5.1) [1, 2]. 

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