Michael-Henry reaction

SCHEME 2.56 Chiral thioureas-catalyzed Michael-Henry reaction for the construction of pyrrolidines. 

SCHEME 2.57 Asymmetric aza-Michael—Henry cascade reaction of 2-aminobenzaldehydes with nitroolefins. 

SCHEME 2.58 Asymmetric synthesis of bicyclo[3.2.1]octan-8-ones via Michael-Hemy 

SCHEME 2.59 Chiral thioureas-catalyzed Michael-Henry process between cyclohexa-1,4-dione and P-nitrostyrenes. 

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Naturally occurring and synthetic polyhydroxylated pyrrolidine and piperidines have recently received considerable attention due to their biological activities. Barco has used tandem Michael-Henry reactions to synthesize 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidines, from which the nitro group is removed to give the natural product, trans 2-hydroxymethyl-3-hy-droxypyrrolidine (Eq. 7.72).91... 

By employing the primary amine catalyst 160, Zhong and coworkers developed the tandem Michael-Henry reaction of ketones with nitroalkenes to provide highly functionalized chiral hexanes and pentanes with high diastereo- and enantioselec-tivity [49]. The selected examples depicted in Scheme 9.56 show that, in the presence of 160 (10-15 mol%), various Michael donors and nitroalkenes smoothly underwent the tandem reaction with almost quantitative yield and extremely high enantios-electivity with the complete diastereoselectivity of the products. Further details of this reaction can be seen in Section 10.4. 

DBU is capable of inducing the elimination of /3-acetoxy nitroalkanes and deprotonation of benzyl isocyanoacetate. A tandem Michael-Henry reaction of the resulting species ensues, leading to 3,4-disubstituted pyrrole-2-carboxylic esters. 

Scheme 7.22 Cascade nitro-Michael/Henry reaction for the formation of cyclohexanes with five stereogenic centers.

Scheme 7.11 Jorgensen s organocatalyzed asymmetric nitro-Michael/Henry reaction.

Scheme 7.12 Hayashi s Michael/Henry reaction to chiral nitrocyclohexanecarbaldehydes.

A domino nitro-Michael/Henry reaction was conceived by Seeberger et al. to afford a 2-nitropyranoside system 156, regarded as an excellent carbohydrate building block (Scheme 7.31) [84]. In this case, the reaction between hydroxyaldehyde 154 and nitroalkene 155 was investigated, with the base liHMDS performing well... 

Also in 2008, Xu et al. [158] developed a novel domino oxa-Michael/Henry reaction of 2-hydroxybenzaldehydes with nitroalkenes, providing the corresponding... 

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-... 

Scheme 11.20 Cu-catalyzed domino Michael/Michael/Henry reaction [31].

Hayashi et al. [39] described, in 2007, a new tandem Michael-Henry reaction that gives rise to chiral cyclohexanes (463) with total control of four stereocenters. The reaction between 2,5-dihydroxy-3,4-dihydrofuran (60) and a different set of nitro-styrenes (28) was efficiently catalyzed by the diphenylprolinol derivative VII, rendering the chiral cyclohexanes (61) in high yields and enantioselectivities (Scheme 10.19). In 2009, Cordova and co-workers [40] reported a similar reaction using alkylidene malonates instead of nitrostyrenes, obtaining the corresponding cyclohexanes with good yields and stereoselectivities. 

Nitrohydroxylated pyrrolidine and piperidine ring systems 1824 have been conveniently obtained by a one-pot procedure involving sequential Michael-Henry reaction between nitroethene and a nitrogen nucleophile 1823 suitably predisposed for the oxidative generation (Swem reaction) of an aldehyde group, which is directly trapped in the subsequent nitroaldolization step [1384]. 

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). 

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... 

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