Ketones Baylis-Hillman reaction

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. 

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 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 ... 

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. 

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... 

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. 

The Baylis-Hillman reaction of TV-protected 3-substituted 4-formylazetidin-2-ones with methyl vinyl ketone has been used to prepare intermediates from which highly functionalised P-lactams fused to medium rings were obtained by radical, stereocontrolled methods <99CC1913>. 

Fluorochromenes result from the reaction of the Cs salts of salicylaldehydes with the phosphonium triflate 37 (Scheme 24) <0OJCS(Pl)103> and 3-acylchromenes are formed from salicylaldehydes and alkyl vinyl ketones in a chemoselective Baylis-Hillman reaction (Scheme 25) . 

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]. 

The Baylis-Hillman reaction (Scheme 3) of ethyl vinyl ketone with electron-deficient aromatic aldehydes (e.g. where R = 0-NO2C6H4), in MeCN or EtCN solution, has been found to proceed enantioselectively in presence of catalytic base (32) derived from proline. The Michael adduct formed between the catalyst and the vinyl... 

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. 

The most efficient catalyst system for the Morita-Baylis-Hillman reaction of methyl vinyl ketone has been reported by Miller [183, 184], Use of L-proline (58) (10 mol%) in conjunction with the A-methyl imidazole containing hexapeptide 131 (10 mol%) provided an efficient platform for the reaction of 125 with a series of aromatic aldehydes 127 (52-95% yield 45-81% ee) (Scheme 52). Importantly, it was shown that the absolute configuration of the proline catalyst was the major factor in directing the stereochemical outcome of the reaction and not the complex peptide backbone. 

The aldehyde can be replaced by an imine and the reaction is then called the aza-Baylis-Hillman reaction [87, 88]. (3-Amino-a-methylene structures obtained in this way could further be converted to a range of biologically important molecules, such as p-amino acids [89]. First reaction of this kind was published in 1984 [90]. Tosylimines and ethylacrylate reacted in the presence of DABCO as catalyst to give p-aminoesters. First three-component aza-Baylis-Hillman reaction was published in 1989 by Bertenshaw and Kahn [91], with imine formation in situ from an aldehyde and an amine. In the presence of triphenylphosphine as catalyst, the reaction with methylacrylate led to the formation of the p-amino-ot-methylene esters and ketones in good yields (Scheme 38). 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

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... 

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... 

The Morita-Baylis-Hillman reaction of chiral glyoxylic acid derivatives with cyclic a,/ -unsaturated ketones proceeded under the catalytic influence of dimethyl sulfide in the presence of titanium tetrachloride [27]. The adducts were obtained with high diastereomeric excess (>95% de) and typical yields around 80%. 

Pyrazole and 3,5-dimethylpyrazole were effective stoichiometric catalysts in the Baylis-Hillman reaction of cyclo-pentenone 892 with /i-nitrobenzaldehyde 893 in basic media to give adducts 894 in good yields (Equation 190) <2004TL5171>. An asymmetric borane reduction of ketones catalyzed by AT-hydroxyalkyl-Z-menthopyrazoles has been reported <2000JHC983>. 3-Aryl-/-menthopyrazoles 895 were assessed for their catalytic activity for asymmetric Diels-Alder reactions <2002JHC1235, 2003JHC773>. 

Shi, M., Zhao, G.-L. One-pot aza-Baylis-Hillman reactions of aryl aldehydes and diphenylphosphinamide with methyl vinyl ketone in the presence of TiCU, PPhs, and EtsN. Tetrahedron Lett, 2002,43, 9171-9174. 

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. 

Shi, M., Xu, Y.-M. An Unexpected Highly Stereoselective Double Aza-Baylis-Hillman Reaction of Sulfonated Imines with Phenyl Vinyl Ketone. J. Org. Chem. 2003, 68, 4784-4790. 

Aldol reactions. Regioselective aldol reaction at a more highly substituted a-position of a ketone is promoted by TiCl. This Lewis acid also catalyzes the Baylis-Hillman reaction participated by dimethyl sulfide. ... 

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. 

The obtained ionic liquid, methyltrioctylammonium dimaloborate, has been used as the only source of chirality in the aza-Baylis-Hillman reaction between methyl vinyl ketone and N-(4-bromobenzylidene)-4-toluenesulfonamide using PPh3 as catalyst, obtaining enantioselectivities up to 84% ee. 

In a breakthrough in IL chemistry directed to applications in asymmetric catalysis using chiral reaction media, Leitner and co-workers developed an enantioselective aza-Baylis-Hillman reaction, where enantiocontrol was ensured by the use of IL 36 as solvent. Scheme 1.17 shows the synthesis of the chiral anion. This is the first example in the literature of ees of the order of magnitude of 85% due to the use of a chiral solvent. The imine and the catalyst (10mol.%) are dissolved in the IL, then methyl vinyl ketone is added and the reaction is simply carried out by stirring at rt for 24 h (Scheme 1.18). 

As a test reaction to determine the activity of this catalyst, the coupling of 4-nitrobenzaldehyde with methyl vinyl ketone, a paradigmatic example of the Baylis-Hillman reaction, was selected. The major product was the corresponding p-hydroxyketone 110 accompanied by minor amounts of the Michael adduct 111 that appeared at high conversions when an excess of methyl vinyl ketone was utilized (Scheme 3.31). 

Another excellent piece of work in this area on the aza-Baylis-Hillman reaction was pnblished by Gausepohl and coworkers [65]. In this process, a C-C bond occurs between an activated alkene and imine. For this purpose, a new malic-add-based ionic liquid (sodium dimalatoborate salt) was designed and synthesized (Scheme 17.17). To assess the efficacy of it for chiral induction, the aza-BayUs-Hillman reaction between methyl vinyl ketone and A-(4-bromobenzylidene)-4-toluenesulfonamide was examined. In this model reaction, a reasonable conversion of 39% and high enantiomeric excess of up to 84% were obtained. 

The Baylis-Hillman reaction is a highly useful and general method for the synthesis of allylic alcohols. A method to convert the product of a Baylis-Hillman reaction to an epoxidized a,P-unsaturated ketone has been reported <05TL8895>. lodosobenzene and KBr... 

Introduction The extended enolate problem Kinetic and thermodynamic control Wittig and Horner-Wadsworth-Emmons Reactions Extended Aza-Enolates Extended Lithium Enolates of Aldehydes Summary a-Alkylation of Extended Enolates Reaction in the y-Position Extended Enolates from Unsaturated Ketones Diels-Alder Reactions Extended Enolates from Birch Reductions The Baylis-Hillman Reaction The Synthesis of Mniopetal F... 

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