2-Mercaptobenzaldehyde domino reactions

The asymmetric domino reactions between 2-mercaptobenzaldehyde and a,fi-unsaturated aldehydes proceed with excellent chemo- and enantio-selectivities in the presence of (99) (20 mol%) as organocatalyst to afford 2//-l-benzothiopyrans (98) in high yields with 91-98% ee.145... 

The asymmetric domino reaction between 2-mercaptobenzaldehyde and a,f)-unsaturated aldehydes proceeds with excellent chemo- and enantio-selectivities to afford 2-substituted 3-formyl-2//-l bcnzothiopyrans, products of a formal Baylis-Hillman reaction, when the. 9-proline derived catalyst 407 is employed (Scheme 123) <2006TL8547>. 

The asymmetric conjugate additions with thiol nucleophiles was further expanded to 2-mercaptobenzaldehydes [98]. Wang had previously developed a domino Michael-aldol reaction promoted by Cinchona alkaloids, and now illustrated the utihty of cyclohexane-diamine bifunctionalized catalysts for the domino... 

Scheme 6.71 Succinimide-containing substituted thiochromanes obtained from the 12-catalyzed enantio- and diastereoselective domino Michael-aldol reaction between 2-mercaptobenzaldehydes and maleimides.

In 2007, Wang and co-workers published a protocol for an enantio- and diastereoselective domino Michael-aldol reaction using electron-rich and electron-deficient 2-mercaptobenzaldehydes and maleimides as substrates [223]. The conversion was described to proceed smoothly in the presence of bifunctional catalyst 12 (lmol% loading) in xylenes at 0°C reaction temperature producing the desired chiral succinimide-containing substituted thiochromanes 1-5 in high yields (83-96%), in synthetically useful ee values (74—94%), and diastereoselectivities (up to dr 20 1) in 7h reaction time (Scheme 6.71). 

The process was efRciently catalyzed by a chiral pyrrolidine in the presence of salicylic acid. It must be noted that Zhao et al. [159] had previously developed, in 2007, a similar reaction for the synthesis of chiral thiochromanes through domino oxa-Michael/Henry reaction of 2-mercaptobenzaldehydes with ititrostyrenes catalyzed by a simple chiral cupreine. The corresponding chiral 2-aryl-3-ititrothiochroman-... 

A closely related methodology was applied by Zhao et al. to the enantio-selective synthesis of tetrasubstituted thiochromanes on the basis of a domino thia-Michael-Knoevenagel reaction between 2-mercaptobenzaldehydes and benzylidenemalonates with the same quinine thiourea catalyst. Steric and electron effects were found to affect profoundly the stereoselectivities of the reaction. Thus, it was shown that the diastereoselectivity of the reaction... 

In the same context, these authors reported the synthesis of chiral 2,3,4-trisubstituted thiochromanes by using a cupreine-catalysed domino thia-Michael-Henry reaction, occurring between 2-mercaptobenzaldehydes and nitrostyrenes. As shown in Scheme 1.82, the resulting products were... 

Alternatively, Wang and coworkers reported a highly enantioselective domino thia-Michael/aldol sequence using bifunctional thiourea-tertiary amine catalysts to afford spirocyclic compound 76 [43]. ( )-Benzylidene chromanone derivatives 74 reacted with 2-mercaptobenzaldehydes 75 in the presence of a bifunctional tertiary amine-thiourea catalyst XVIII. The thia-Michael addition to the benzylidene was followed by an intramolecular aldol reaction between the resulting enolate and the aldehyde moiety. As shown in Scheme 10.26, the reaction afforded the highly functionalized spirocycles in excellent yields and stereoselectivities. 

The asymmetric conjugate addition with thiol nucleophiles was demonstrated using 2-mercaptobenzaldehydes. The utiUty of the same chiral cyclohexane-diamine catalysts 35 mediated the domino Michael-aldolof 2-sulfanylbenzaldehydes with maleimides (Scheme 13.10) [28]. The products of the reaction consist of fused heterocycles in high yield and high enantiomeric ratios. The stereochemical outcome sheds insight into the proposed mechanism whereby the catalyst simultaneously activates the thiol group via the cyclohexyl tertiary amine while the maleimide is stabilized by the thiourea component... 

Cinchona-alkaloid-catalysed conjugate cyanation of enones has enabled the synthesis of trifluoromethyl-substituted diarylpyrroles with ee<96%P° Thiochro-manes have been formed by asymmetric domino sulfa-Michael-aldol reactions of 2-mercaptobenzaldehyde with a,/ -unsaturated A-acylpyrazoles. Asymmetric organocatalysed oxy-Michael addition to y-hydroxy a,/ -unsaturated thioesters on reaction with t-BuCHO has been used to form -hydroxy carbonyl compounds HOCH2C H(OH)CH2CO.SAr via cyclic hemiacetal intermediates. 

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