Baylis-Hillman alcohols

This particular stereochemical outcome observed with Baylis-Hillman alcohols 75a and 75b can be explained by a predominant 1,3-diaxial interaction with alkyl groups that shift the conformational equilibrium to transition state 78b, whereas an 1,2-allylic strain is more prominent with aryl groups and favor transition state 78c (Scheme 6.10). 

Baylis-Hillman alcohols and their derivatives represent a particularly useful group of regents widely utilized in the synthesis of a-aUcylidene y and 8-lactones and lactams. These attractive synthetic intermediates easily undergo alkylation reactions of various nucleophiles resulting in the introduction of ester and alkylidene moieties into the target molecules. 

In a similar manner, simple Baylis-Hillman alcohols 62 were transformed into P,y-disubstituted-a-methylene-y-lactams 29b (Scheme 4.16) [48]. The sequential treatment of alcohols 62 with HBr, DABCO (l,4-diazabicyclo(2.2.2]octane), and a nitroalkane 51 afforded the requisite 2-methylene-4-nitroalkanoates 63 as two diastereoisomers in a 1 1 ratio. Subsequent standard transformations involving reduction of the nitro group and lactamization gave the final products 29b as mixtures of two diastereoisomers with the ratio originating from the substitution... 

Scheme 4.16 Synthesis of p,y-disubstituted-a-methylene-y-lactams 29b from Baylis-Hillman alcohols 62.

Yadav LDS, Awasthi C. The first one-opt oxidative 1,2-ace-toxysulfenylation and 1, 2-disulfenylation of Baylis-Hillman alcohols in an ionic liquid. Tetrahedron Lett. 2009 50 3801-3804. 

The t/z/a-Michael addition followed by an intramolecular cyclisation were used as key reactions in an efficient, one-pot, diastereoseletive synthesis of 3-nitrothietanes (82) and (83). Thus, Baylis-Hillman alcohols (79) and the coresponding aldehydes (80) were reacted with diethyl phosphorodithioate (81) itself or in a combination with a task-specific ionic liquid to afford the corresponding 2,3-di- and 2,3,4-trisubstituted thietanes, (82) and (83), with complete diastereoselectivity in favour of the tram isomers (Scheme 27). ... 

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. 

Racker et al. have developed an interesting new combinatorial method for the synthesis of [l,4]oxazepin-7-ones (eg 139, R = Ph) from aldehydes and a-amino alcohols with the Baylis-Hillman reaction being a key step . 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

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. 

Kissel, Ramsden, and other researchers at Pfizer and Chirotech jointly published a novel chiral synthesis of pregabalin (2) in 2003 based on asymmetric hydrogenation (Burk et al., 2001, 2003). Their synthesis started with the condensation of isobutyralde-hyde with acrylonitrile under Baylis-Hillman conditions to give allylic alcohol 65. This alcohol was activated as the carbonate 66 and subjected to palladium-catalyzed car-bonylation conditions to give cyanoester 67. The ester 67 was hydrolyzed and converted to... 

Ab initio calculations also confirm that the use of an allyl magnesium alkoxide in place of the alcohol functionality will lead to high or complete stereoselectivity (138). When homoallylic alcohols are used, the Kanemasa protocol afforded the respective isoxazolines with poor stereoselectivity ( 55 45) in the case of terminal aUcenes, but with very high diastereoselectivity (up to 96 4) in the reaction of cis-1,2-disubstituted olefins (136). Extension of this concept to the reaction of a-silyl allyl alcohols also proved feasible and produced the syn (threo) adducts as nearly pure diastereomers (>94 6) (137). Thus, the normal stereoselectivity of the cycloaddition to the Morita-Baylis-Hillman adducts (anti > syn, see above) can be reversed by prior addition of a Grignard reagent (176,177). Both this reversal... 

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). 

Boron enolates bearing menthol-derived chiral ligands have been found to exhibit excellent diastereo- and enantio-control on reaction with aldehydes34 and imines.35 Highly diastereo- and enantio-selective aldol additions of geometrically defined trichlorosilyl ketone enolates (31) and (32) have been achieved by promoting the reactions with chiral Lewis bases, of which (,S., S )-(33) proved to be the most effective.36 Moderate enantiomeric excesses have been achieved by using chiral ammo alcohols as catalysts for the Baylis-Hillman condensation of aldehydes with methyl vinyl ketone the unexpected pressure effect on the reaction has been rationalized.37... 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

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... 

Sato and coworkers have reported an asymmetric synthesis of Baylis-Hillman-type allylic alcohols 48, 49 via a chiral acetylenic ester titanium alkoxide complex (Scheme 9) [41]. These reactions rely on the use of the novel acetylenic ester titanium alkoxide complex 44 with a camphor-derived chiral auxiliary. Optically active, stereodefined hydroxy acrylates 46, 47 were obtained in high yields and with excellent regio- and diastereoselectivities. The chiral auxiliary was subsequently cleaved off by alcoholysis. 

Azetidinones with a 4-allyl alcohol substituent, for example, 309, which are readily available from /3-lactam 4-aldehyde by the Baylis-Hillman reaction, are converted by triphenyltin hydride plus AIBN without racemization in good yield to fused ring systems, 310 (n = 1-3). 

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]. 

The Morita-Baylis-Hillman (MBH) reaction - the reaction of an electron-deficient alkene with an aldehyde or an imine (aza-MBH) - provides a convenient route to highly functionalized allylic alcohols and amines. Although the reaction is catalyzed by simple amines or phosphines, its scope is somewhat limited due to slow reaction rates. The MBH reaction is discussed fully in Chapter 5, and consequently only those contributions that clearly involve hydrogen bond interactions will be described here. 

Azocanes with nitrogen at a bridgehead such as fused azocane 289 were prepared starting from /V-protected amino aldehydes 286. Those amino aldehydes were converted into allylic alcohols by the classical Morita-Baylis-Hillman reaction or by condensation with selenium-stabilized carbanions, followed by oxidation <2007JOC5608>. Fused azocane 289 was prepared in good yield as described in Scheme 120. Formation of [ z, ,0]-bicyclic structures via these reactions is general and the stereochemistry of the starting amino-aldehyde is preserved. 

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