Domino Michael/Henry

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). 

The asymmetric Henry reaction has been reviewed, " and a survey of organocat- 0 alytic enantioselective versions includes recent advances in the emergent domino Michael/Henry protocol. 0... 

Scheme 2.40 Domino Michael/Henry reaction of 1,2-diones with nitroalkenes catalysed by an in situ generated diamine nickel catalyst.

In 2014, Arai and Yamamoto described asymmetric nickel-catalysed domino Michael/Henry reactions between 2-sulfanylbenzaldehydes and aromatic nitroalkenes to give the corresponding chiral 2-aryl-3-nitrochroman-4-ols, in most cases in almost quantitative yields and with good to high diastereo- and enantioselectivities of up to >98% de and 95% ee, respectively (R = H, Scheme 4.4). These reactions were promoted by an in situ generated catalyst from 10-11 mol% of chiral imidazoline-aminophenol ligand 1 and... 

Scheme 4.3 Domino Michael/Henry reaction of cyclohexane-1,2-dione with nitroalkenes.

Finally, Sankararaman et al. have reported the synthesis of chiral nitro-chromenes on the basis of an asymmetric domino Michael-Henry reaction followed by dehydration, involving nitrostyrene and orlho-hydio-xybenzaldehyde. This reaction was catalysed by a novel C2-symmetric bis-(pyrrolidine-triazole)-based organocatalyst and provided only moderate yields (22-40%) and poor enantioselectivities (7-24% ee). 

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]. 

Tsakos, M., Elsegood, M. R. J., Kokotos, C. G. (2013). Organocatalytic asymmetric domino Michael-Henry reaction for the synthesis of substituted bicyclo[3.2.1]octan-2-ones. Chemical Communications, 49, 2219-2221. 

A protonated O-TMS-diphenylproUnol 103/BzOH catalytic system was used by Ni et al. in an asymmetric domino Michael/Henry reaction in an aqueous medium. Chiral Michael adducts 107 generated in situ from pentane-1,5-dial (106) and (i-nitrostyrene derivatives spontaneously underwent an intramolecular Henry reaction under the proposed conditions to afford 3-substituted 2-nitro-4-formylcyclohexanols 108 containing four stereocenters in moderate to high yields and with almost complete enantioselectivity (Scheme 22.31) [116]. The catalyst could be recycled at least four times, with only a slight reduction in yields and diastereoselectivity. 

Scheme 37.10 Synthesis of biq clo[3.2.1]octan-8-ones through a domino Michael-Henry reaction.

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]. 

Scheme 22.31 Domino Michael/Henry reaction catalyzed by 103/BzOH.

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