Asymmetric aza-Baylis—Hillman

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. 

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. 

Whilst we were synthesizing (R,R,/ ax)-20a and (5,5,l ax)-20b, RajanBabu and Saha reported their use in the catalytic hydrovinylation of styrene derivatives [66]. However, their 16% yield of the preceding primary phosphine can be improved to quantitative levels [38, 39] by using lithium aluminum hydride in conjunction with chlorotrimethylsilane, and their 5% yield of the phospholanes can now be rationalized at least in part by our isolation of the phenolic compounds R,R,R )-2 a and (5,5,/ ax)-21b. These phenolic phospholanes should prove to be interesting L-X ligands in their own right the parent 2-diphenylphosphino derivative has already been shown to be an effective chiral base in the asymmetric aza-Baylis-Hillman transformations of A-sulfonated imines, by virtue of its phenolic residue [67]. 

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... 

Silyl ketene imines have been acylated asymmetrically by anhydrides evidence for a silyl-free nitrile anion intermediate is discussed.86 An aza-Baylis-Hillman reaction of N-sul fonated imines is described below. 

Balan, D., Adolfsson, H. Chiral quinuclidine-based amine catalysts for the asymmetric one-pot, three-component aza-Baylis-Hillman reaction. Tetrahedron Lett, 2003, 44, 2521-2524. 

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). 

However, despite the rapid design of news CILs, successful applications in synthesis remained elusive for some time. Only in the last 2-3 years have some significant results been obtained. Leitner and co-workers in 2006 reported a high enantiomeric excess (84% ee) by using a chiral anion containing ionic liquid for an aza-Baylis-Hillman reaction (Scheme 4.11), whereas CILs with an imidazolium or a benzimidazolium unit attached to (5)-pyrrolidine have been used with success as solvents or catalysts for asymmetric aldol reactions and Michael additions to nitroolefins (ee up to 99%). ... 

In addition to tertiary amines, triphenylphosphine is also an effective promoter and the use of enantiomerically pure amines or phosphines to catalyse the reaction is an interesting prospect, since the products would be synthetically useful. In addition there is also the potential for Lewis acid/Bronsted acid-catalysed asymmetric MBH reactions. While early attempts at the development of a catalytic asymmetric variant were only moderately successful, providing products with up to 50% ee, some recent progress has been made in this area and high ees have been obtained in both the MBH and aza-Baylis-Hillman reaction of a,p-carbonyls with imines. 

Recent advances in organocatalytic asymmetric Morita-Baylis-Hillman reactions and their aza-variants have been reviewed (112 references), with a particular focus on amine- and phosphine-catalysed routes, and bifunctional catalysis. 0... 

Other successful H-bond catalysis apphcations have been introduced by Schaus and Sasai involving asymmetric Morita-Bayhs-Hilhnan (Scheme 11.13c) and aza-Morita-Baylis-Hillman reactions (Scheme 11.13d), respectively. Intriguingly, derivatized BINOL systems 33 and 34 provided optimal selectivities. 

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

Asymmetric aza Morita-Baylis-Hillman reactions of N-sulfonylimines or N-sulfinimines with Michael accepters in the presence a Lewis base catalyst to give the corresponding chiral a-methylene-/ -amino compounds have been described [27]. 

Chiral Amines Derived from Asymmetric Aza Morita Baylis Hillman Reaction... 

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