Sulfa-Michael/aldol cascade reaction

The construction of polyheterocycHc spirotetrahydrothio derivatives via a sulfa-Michael/aldol cascade reaction appeared in the literature in the year 2014 (14TL6335).The authors were attraaed to tetrahydrothiophenes due to their ability to serve as building blocks in many pharmaceutical agents and natural products. Previously, methods for preparing tetrahydrothiophenes lacked generality and efficiency. These workers were able to prepare titled compounds by the reaction of various chalcones with 1,4-dithane-2,5-diol under mild conditions. A few examples are shown below.The latter reaction showed excellent diasteroselectivity in the presence of a chiral phase transfer catalyst. 

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]. 

Using this approach, benzothiopyrans have been prepared by means of a sulfa-Michael/aldol/dehydration cascade and access to dihydroquinolines has been achieved by using an aza-Michael/aldol/dehydration approach (Scheme 7.52). In general, all these reactions proceeded with excellent yields and... 

Scheme 7.71 One example of a cascade sulfa-Michael/aldol reaction catalyzed by a chiral thiourea.

In addition to conventional Diels-Alder reactions, consecutive [4-1-2] reactions have been subjected to extensive investigation through the iminium-enamine catalytic sequence. Wang, Rios, and others simultaneously described enantioselective cascade sulfa-, oxa-, and aza-Michael/aldol/dehydration reactions promoted by chiral secondary amines. An initial strategy for a one-pot synthesis of chiral thiochromenes with good to high enantioselectivities was reported (Schemes 1.46 and 1.47) [71]. 

In a continuation of enantioseleclive cascade sulfa-, oxa-, and aza-Michael/aldol/ dehydration cascade reactions, Wang et al. envisioned that the employment of a nucleophilic carbon atom for the initial Michael addition could enable the generation of two new C—C bonds in sequential [3+2] reactions. 

---