Thiourea enantioselective Baylis-Hillman reactions

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... 

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.)...

The cooperative effect of Brpnsted acid catalysts and thiourea catalysts has been noticed by the Shi group (Fig. 18) [74]. In their 2007 paper on chiral thiourea-phosphine catalyzed asymmetric aza-Morita-Baylis-Hillman reaction, Shi and co-workers described that when they used a freshly prepared 77-benzylidene-4-methylbenzenesulfonamide substrate, much lower yield and enantioselectivity of the aza-Morita-Baylis-Hillman product was obtained compared with their initial result when using a long-stored substrate. They subsequently found that the long-stored substrate contained a small amount of 4-methylbenzenesulfonamide and... 

Bis-thiourea catalysts have been developed by several research groups. Nagasawa et al. synthesized chiral bis-thiourea derivatives and demonstrated their catalytic activity in the Michael reaction of pyrrolidone, giving rise to a,p-unsaturated y-lactones with moderate enantioselectivity [80]. trans-l,2-Diaminocyclohexane-derived bis-thiourea (5) promoted the DMAP mediated Baylis-Hillman reaction to give the adducts with high enantioselectivity (Scheme 2.30) [81]. 

A novel bifunctional thiourea catalyst (11), bearing binaphthyl backbone, was synthesized by Wang et al They reported enantioselective Morita-Baylis-Hillman reaction of cyclohexenone with a range of aldehydes by means of (11) (Scheme 2.45) [98]. 

The influence of pressure on organic reactions catalyzed by chiral metal-free organic molecules was studied for selected asymmetric Michael, Baylis-Hillman, aldol, Mannich, Friedel-Crafls, and Diels-Alder reactions-the essential part of this work was done in Japan. In the early stages of those investigations the high-pressure technique was applied to reactions catalyzed by cinchona alkaloids and in most cases low or moderate enantioselectivities were observed. Since 2002 some examples of high-pressure reactions catalyzed by proUne, thioureas, and modified cinchona alkaloids have appeared. 

The asymmetric allylic substitution reaction of Morita-Baylis-Hillman carbonates (226) with diphenyl phosphite in the presence of chiral multifunctional thiourea-phosphine catalyst (228) provided allylic phosphites (227) in high yields and with excellent enantioselectivities (Scheme 76). 

---