Reactions Baylis-Hillman

DABCO was used in this reaction, and only the fluorous thiourea was recovered by fluorous solid-phase extraction. 

the starting materials are commercially available and the reaction is suitable for large-scale production  

The Chemistry of the Morita-Baylis-Hillman Reaction By Min Shi, Fei-Jun Wang, Mei-Xin Zhao and Yin Wei Min Shi, Fei-Jun Wang, Mei-Xin Zhao and Yin Wei 2011 Published by the Royal Society of Chemistry, www.rsc.org 

usually involves a nucleophilic organocatalytic system without the heavy-metal pollution  

Although several major reviews have discussed MBH/aza-MBH reaction and their applications in synthesis, it was difficult to completely overview the chemistry of MBH reaction due to a boom of research results in recent years. We hope that this book will satisfy the expectations of readers who are interested in the development of the field and looking for complete and up-to-date information on the chemistry of MBH reaction. 

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

Broadwater, S. J. Jung, H. M. McQuade, D. T. Org. Lett. 2005, 7, 147. A novel mechanism involving a hemiacetal intermediate is proposed. 

E2 (bimolecular elimination) mechanism is also operative here  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 15, Springer-Verlag Berlin Heidelberg 2009 

Limberakis, C. Morita-Baylis-Hillman reaction. In Name Reactions for Homologa-tions-Part I Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 350-380. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 18, Springer International Publishing Switzerland 2014 

Baylis, A. B. Hillman, M. E. D. Ger. Pat 2,155,113, (1972). Both Anthony B. Baylis and Melville E. D. Hillman were chemists at Celanese Coip. USA. 

Krishna, P. R. Narsingam, M. Kannan, V. Tetrahedron Lett. 2004, 45, AlTi-4115. 

The currently accepted mechanism of the Baylis-Hillman reaction involves a Michael addition of the catalyst (tertiary amine) at the (3-position of the activated alkene to form a zwitterionic enolate. This enolate reacts with the aldehyde to give another zwitterion that is deprotonated, and the catalyst is released. Proton transfer affords the final product. 

Hatekayama and co-workers developed a highly enantio- and stereocontrolled route to the key precursor of the novel plant cell Inhibitor epopromycin B, using a cinchona-alkaloid catalyzed Baylis-Hillman reaction of A/-Fmoc leucinal.  

It was shown in the laboratory of P.T. Kaye that the reactions of 2-hydroxybenzaldehydes and 2-hydroxy-1-naphthaldehydes with various activated aikenes proceeded with regioseiective cyclization under Baylis-Hillman conditions to afford the corresponding 3-substituted 2H-chromene derivatives in high yields. Previous attempts to prepare 2H-chromenes chemoselectively via the cyclization of 2-hydroxybenzaldehyde-derived Baylis-Hillman products had proven unsuccessful. Complex mixtures containing coumarin and chromene derivatives were obtained. Good results were observed after the careful and systematic study of the various reactants and reaction conditions. 

Basavaiah and co-workers achieved the simple and convenient stereoselective synthesis of ( )-a-methylcinnamic acids via the nucleophilic addition of hydride ion from sodium borohydride to acetates of Bayiis-Hillman adducts (methyl 3-acetoxy-3-aryl-2-methylenepropanoates), followed by hydrolysis and crystaliization. The potential of this methodology was demonstrated in the synthesis of ( )-p-(myristyloxy)-a-methylcinnamic acid, which is an active hypolipidemic agent. 

Research by J. Jauch showed that in the case of highiy base-sensitive substrates the Baylis-Hillmann reaction can be carried out by using lithium phenylselenide, which is a strong nucieophile but oniy weakiy basic. This variant of the reaction is highly diastereoselective and was successfully applied to the total synthesis of kuehneromycin 

CaiTuthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, Cambridge, 1986, p. 263-279. 

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 reaction starts with the nucleophilic addition of a tertiary amine 4 to the alkene 2 bearing an electron-withdrawing group. The zwitterionic intermediate 5 thus formed, has an activated carbon center a to the carbonyl group, as represented by the resonance structure 5a. The activated a-carbon acts as a nucleophilic center in a reaction with the electrophilic carbonyl carbon of the aldehyde or ketone 1  

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  

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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 intramolecular variant of the Baylis-Hillman reaction is also possible, and may be used for the construction of functionalized ring systems, e.g. a cyclopen-tene derivative such as 12. However, good yields have been achieved in only a few cases ... 

The Baylis-Hillman reaction is usually carried out under mild conditions (0°C or room temperature). The reaction time varies from a few minutes to even days. With the proper catalyst, good yields are possible. In the absence of an aldehyde or ketone as the electrophilic component, a dimerization of the activated alkene can take place under the influence of the catalyst, as also observed as a side reaction under the usual reaction conditions ... 

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... 

Addition of conjugated alkenes to aldehydes (the Baylis-Hillman reaction)... 

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]. 

Other catalysts have also been used. In aqueous media, imidazole was found to catalyze Baylis-Hillman reactions of cyclopent-2-enone... 

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... 

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... 

The reaction of 4-95 to give a 96 4-mixture of 4-96 and 4-97 containing the central core of 4-94 was performed by heating 4-95 for 67 h at 40 °C and then adding PMe3 to induce the Morita-Baylis-Hillman reaction (Scheme 4.21). 

In the next step of the sequence, the authors sought to introduce a hydroxy-methylene substituent at the unsubstituted 7-position of the enone. This bond construction can be carried out by conducting a Baylis-Hillman reaction with formaldehyde. In this instance, the authors used a modification of the Baylis-Hillman reaction which involves the use of a Lewis acid to activate the enone [26]. Under these conditions, the enone 42 is treated with excess paraformaldehyde in the presence of triethylphosphine (1 equiv), lanthanum triflate (5 mol%), and triethanolamine (50 mol%). It is proposed that the lanthanum triflate forms a complex with the triethanolamine. This complex is able to activate the enone toward 1,4-addition of the nucleophilic catalysts (here, triethylphosphine). In the absence of triethanolamine, the Lewis acid catalyst undergoes nonproductive complexation with the nucleophilic catalyst, leading to diminution of catalysis. Under these conditions, the hydroxymethylene derivative 37 was formed in 70 % yield. In the next step of the sequence, the authors sought to conduct a stereoselective epoxidation of the allylic... 

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... 

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. 

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>. 

An interesting combination of ring-closing metathesis chemistry with the aza-Baylis-Hillman reaction has recently been described by Balan and Adolfsson and is shown in Scheme 6.70 a [149]. The authors reported that functionalized 2,5-dihydro-... 

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