Michael/Henry tandem reaction

Jia, Z.-X., Luo, Y.-C., Xu, P.-F. (2011). Highly enantioselective synthesis of polysub-stituted tetrahydroquinolines via organocatalytic Michael/Aza-Henry tandem reactions. Organic Letters, 13, 832-835. 

This synthetic feat relies on an asymmetric Michael/Michael/Henry tandem sequence, resulting in a formal [24-24-2] cycloaddition. The generation of a chiral copper enolate, which undergoes two successive Michael additions on two nitroalkenes followed by ring closure with a Henry reaction, generates the expected adduct in a highly enantio- and diastereoselective manner (Scheme 7.14). 

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... 

Another approach employing chiral acyclic azomethine ylides was published in two recent papers by Alcaide et al. (85,86). The azomethine ylide-silver complex (51) was formed in situ by reaction of the formyl-substituted chiral azetidinone (50) with glycine (or alanine) in the presence of AgOTf and a base (Scheme 12.18). Azomethine ylides formed in this manner were subjected to reaction with various electron-deficient alkenes. One example of this is the reaction with nitrostyrene, as illustrated in Scheme 12.18 (86). The reaction is proposed to proceed via a two step tandem Michael-Henry process in which the products 52a and 52b are isolated in a... 

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. 

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. 

Scheme 2.34 Tandem Henry-Michael-retro-Heniy reaction catalysed by a chiral cinchona alkaloid thiourea and 1,1,3,3-tetramethyl guanidine.

Finally, a remarkable four-component tandem Michael-aza-Henry-hemi-aminalisation-dehydration tandem reaction was recently developed by Lin and co-workers on the basis of a dual organocatalysis involving a chiral diaryl prolinol trimethylsilyl ether and a chiral cinchona alkaloid." As shown in Scheme 2.37, the reaction began with the Michael addition of an aldehyde to a nitroalkene catalysed by the L-proline-derived catalyst, giving the corresponding intermediate aldehyde. The latter intermediate... 

Most recently, Xu et al. have demonstrated the first example of a diastereo-and enantioselective aza-MBH-type reaction by the asymmetric synthesis of p-nitro-y-enamines via a (li ,2i )-diaminocyclohexane thiourea derivative (182) mediated tandem Michael addition and aza-Henry reaction in good yields (up to 95%) with high enantioselectivities (up to 91% ee) and diastereoselectivities (up to 1 99 dr) (Scheme 2.90) easily prepared A -tosylimines and nitroalkene are employed as the starting materials. ... 

Catalyst 5-Hydroxypentylammonium acetate (5-HPAA reusable task-specific ionic liquid) Keywords Alkyl/aryl/heteroaryl aldehydes, nitromethane, trialkylphosphites, 5-HPAA, solvent-free, room temperature, one-pot tandem Henry-Michael reaction, multicomponent reaction, terminal vinylphosphonates... 

Oxo-hept-5-enals undergo an organocatalytic one-pot reaction with nitromethane to give trisubstituted cyclohexanols with three contiguous chiral centres de of >98% is reported and ee up to 96%. The process is a tandem Henry-Michael, followed by a 0 tandem retro-Henry-Henry. Consistent with this sequence is the finding that the use of 0 the racemic Henry product as substrate gives similar final results. 

In 2013, Zhao et al. described a highly diastereo- and enantioselective synthesis of trisubstituted cyclohexanols based on a one-pot sequential tandem Henry-Michael reaction catalysed by a combination of a chiral cinchona alkaloid thiourea and 1,1,3,3-tetramethyl guanidine. This process occurred between nitromethane and 7-oxo-hept-5-en-l-als, providing the corresponding tandem chiral products as almost single diastereomers... 

Scheme 2.37 Four-component tandem Michael-aza-Henry-hemiaminalisation-dehydration reaction catatysed by a chiral diaiylprolinol trimethyl-silyl ether and a chiral cinchona alkaloid catalyst.

Scheme 7.70 Tandem Henry-oxa-Michael reaction catalysed 1 chiral copper catalysis and camphorsulfonic acid catalysis.

In addition, catalyst 28 has been appUed in an organocatalytic asymmetric tandem Michael/aza-Henry reaction between chalcone derivatives and nitrometh-ane to afford the corresponding polysubstituted tetrahydroquinoline derivatives with good yields and high enantio- and diastereoselectivities [40]. 

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