Aza-Baylis-Hillman reactions

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-... 

Recently the group of Leitner was able to achieve high enantioselectivities in the aza-Baylis-Hillman reaction by the application of enantiopure ionic liquid with a chiral anion (Scheme 82) [208]. 

Scheme 82 Enantioselective aza-Baylis-Hillman reaction in a chiral anion based ionic liquid...

Scheme 38 The first reported three-component aza-Baylis-Hillman reaction [91]...

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). 

The conversion rate in aza-Baylis-Hillman reactions is generally low, which leads to extended reaction times [87]. Heating is normally used to increase the reaction speed however, it also promotes the formation of side products. Alternatively, microwave heating was successfully used as a way of promoting the reaction [92]. However, microwaves-promoted reactions are not easy to scale-up. Guided by this, the Stevens research group [89, 93] used the commercial CYTOS College System [18] to perform these reactions on a microscale in a continuous manner in order to improve the reaction rates and make it industrially more applicable. 

Shi Y-L, Shi M (2007) Aza-Baylis-Hillman reactions and their synthetic applications. Eur J Org Oieni 18 2905-2916... 

Chiral solvents rarely induce significant enantioselectivity, but ees up to 84% have been achieved in an aza-Baylis-Hillman reaction.161 Using an ionic liquid (IL), the anion of which is a dimalatoborate (54), it is suggested that the high enantioselectivity arises from strong ion-pair and hydrogen bond interactions with the zwitterionic intermediate of the reaction, i.e. IL-B- R3P+-CH2-CH=C(Me)-0 HO-IL. 

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... 

Balan and Adolfsson [28] reported a direct catalytic enantioselective three-component aza Baylis-Hillman reaction between arylaldehydes, tosylamides, and Michael acceptors using the quinidine-based Hatekayama catalyst 96 [29] together with titanium isopropoxide as a Lewis acid cocatalyst (Scheme 9.18). High chemical yields and stereoselectivity ranging between 49 and 74% ee were obtained using various substituted arylaldehydes. 

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. 

An NMR kinetic study of a phosphine-catalysed aza-Baylis-Hillman reaction of but-3-enone with arylidene-tosylamides showed rate-limiting proton transfer in the absence of added protic species, but no autocatalysis.175 Brpnsted acids accelerate the elimination step. Study of the effects of BINOL-phosphinoyl catalysts sheds light not only on the potential for enantioselection with such bifunctional catalysis, but also on their scope for catalysing racemization. 

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., 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. 

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. 

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. 

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). 

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%). ... 

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.)...

Allylic amines can be prepared from imines in the Aza-Baylis-Hillman reaction. 

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. 

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