Aldehydes sulfa-Michael reactions

The first organocatalytic sulfa-Michael reaction of enals was reported by j0rgensen in 2005 [68]. In this report aliphatic and aromatic aldehydes reacted with several thiols in good yields and enantioselectivities under catalysis of 28. The products must be reduced immediately due to their fast epimerization at room temperature (Scheme 33.21). In this work, j0rgensen and coworkers also developed several multicomponent cascade reactions with good to excellent results. 

The one-pot, organocatalytic Hayashi sequential reaction (HSR) of p-nitroacrylate (806), aldehyde (807), toluenethiol (808), and vinylphosphonate (805) allowed the synthesis of highly functionaKsed cyclohexanes (809) with very high enantioselectivity (up to 99 % ee). The one-pot synthesis consisted of the tertiary amine modified diarylprolinol silyl ether (810)-mediated asymmetric Michael reaction, a domino Michael reaction/the Horner-Wadsworth Emmons reaction, and a sulfa-Michael reaction (Scheme 205). ... 

Chiral tetrahydrothiophenes are compounds displaying important biological activities. They were obtained also through an enantioselective domino sulfa-Michael-Michael process of a,(3-unsaturated aldehydes with ethyl 4-mercapto-2-butenoate [47]. While catalyst 17a turned out to be ineffective, the diarylprolinol silyl ether 17b afforded cyclic products with high to excellent enantio- and diastereoselectivity (Scheme 14.16a). A closely related sulfa-Michael aldol process was developed by using 3-mercapto a-carbonyl esters as reaction partners. The best stereoselectivity and yield were obtained with diaryl prolinol 17c in the presence of small amounts of H2O (Scheme 14.16b) [48]. 

Wang et al. [49] obtained enantioenriched thiochromenes through a cascade sulfa-Michael-aldol-dehydration reaction between 2-mercaptobenzaldehydes and a,p-unsaturated aldehydes, catalyzed by 17a (Scheme 14.17a). Cordova and coworkers [50] obtained comparable results despite some minor changes of the reaction conditions. An analogous process with cyclic enones afforded tetrahydrothioxanthe-nones in only moderate enantioselectivities (Scheme 14.17b). In this case, chiral pyrrolidines 18 and 19 gave the best results in terms of enantioselectivities [51]. 

Whereas secondary amines are suitable catalysts for activation of a,(3-unsaturated aldehydes, more difficulties are usually encountered with sterically demanding substrates, such as a,(5-unsaturated ketones. Primary amines can be useful catalysts in such cases. Yoshida et al. [52] reported an amino acid-catalyzed sulfa-Michael addition of arylmethyl mercaptans to cyclic enones. The proposed mechanism invokes the formation of an imine intermediate. However, even with the best screened catalyst, 5-trityl L-cysteine, the reaction proceeded with modest levels of enantioselectivity (8-58% ee). 

Scheme 42.14 Organocatalytic MCRs of a-branched a,p-unsaturated aldehyde enals by way of an iminium ion/enamine sequence Friedel-Crafts/amination strategy and sulfa-Michael/ amination strategy. Protocol point all substrates added at the outset of the reaction.

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