Domino Michael/Henry process

Dinitroalkanes (33) were recently used in combination with unsaturated aldehydes (62) for the organocatalytic synthesis of pentasubstituted cyclohexanes (63) by an asymmetric domino Michael/Henry process, which is shown in Figure 2.21 (Reyes et al., 2007). 

Organocatalytic asymmetric reaction between 1,4-cyclohexanedione and nitroalkenes afford bicyclo-[3.2.1]octane derivatives containing four contiguous stereogenic centers (Scheme 6.41). The product formation involves a domino Michael-Henry process using a proline-based bifunctional catalyst. The reaction gives good selectivity and yield in THF, and 4-nitrobenzoic acid is the most effective additive for this transformation [46]. 

Employing cyclohexa-l,4-dione derivative 215 as the nucleophile. Tan et al. developed a thiourea-catalyzed domino Michael-Henry process with p-nitrostyrenes, constructing bicyclo[3.2.1]octane derivatives 216 with highly enantio- and diastereo-selectivities (Scheme 2.59) [85]. 

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-... 

In another context, Frechet et al. have described a polarity-directed three-component domino Henry-Michael reaction of two aliphatic aldehydes with different polarities and nitromethane catalysed by a combination of chiral diphenylprolinol trimethylsilyl ether and L-proline. In this original process. 

Another enantioselective approach to tetrahydroquinolines (compounds 87) was developed by Xu and is based on a Michael-aza-Henry domino process, which is shown in Scheme 3.26 [68]. The reactions were catalyzed by a bifunctional thiourea 86 and proceeded in excellent yields and enantioselectivities, with diastereomeric excesses of up to 90%. 

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