Nitro-Michael/Henry reaction

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.

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... 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

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... 

If an unsaturated aldehyde was combined with a 1,3-dinitro compound, chiral cyclohexanes were formed by a nitro-Michael/Heniy reaction sequence. Miehael addition followed by double Heniy reaction also led to ehiral eyelohexane derivatives. In another application of the Henry re-aetion, Hayashi used nitroalkenes with pentane-l,5-dial (generated in situ) to form ehiral eyelohexane carboxaldehydes. Chiral cyclopentanes were also eonstrueted in another manner. Enamine-mediated Michael addition of aldehydes to 5-iodo-l-nitropent-l-ene led to an intermediate enamine, which underwent intramoleeular cyclisation via iodide displacement. ... 

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. 

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). 

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. 

From the foregoing it can be seen that the nitro group can be activated for C-C bond formation in various ways. Classically the nitro group facilitates the Henry reaction, Michael addition, and Diels-Alder reaction. Komblum and Russell have introduced a new substitution reaction, which proceeds via a one electron-transfer process The Spj l reactions have... 

The stereoselective intramolecular Henry reactions have been reported by Seebach. The Michael addition of doubly deprotonated acetyl acetaldehyde to l-methylenedioxyphenyl-2-nitroethene followed by subsequent intramolecular nitro-aldol cyclization leads to the diastereomerically pure cyclohexanone derivative, where the nitro and OH groups are cis as shown in Eq. 3.73.114 This reaction is applied to the synthesis of l-desoxy-2-lycorinone as shown in Eq. 3.74.115... 

The Michael addition of nitroalkanes to election-deficient alkenes provides a powerful synthetic tool in which it is perceived that the nitro group can be transformed into various functionalities. Various kinds of bases have been used for this transformation in homogeneous solutions, or, alternatively, some heterogeneous catalysts have been employed. In general, bases used in the Henry reaction are also effective for these additions (Scheme 4.18).133... 

Allylic nitro compounds undergo [2.3]sigmatropic rearrangement to afford rearranged alcohols, as shown in Eq. 7.4346 and Eq. 7.44 47 Because the allylic nitro compounds used in these reactions are readily prepared either by the Henry reaction or the Michael addition, these reactions may be useful in organic synthesis. 

Michael additions to sugar nitro olefins have received considerable less attention than the Henry reaction involving nitro sugars. Early examples of Michael addition include the synthesis54 of licoricidin by Paulsen in 1982, the addition of phosphorous nucleophiles to a D-glucose based nitro olefin55 by Yamashita in 1987 and the synthesis of the natural antibiotic polyoxin published by Barret in 1990.56... 

The nitro group activates aliphatic systems and makes possible a number of addition reactions such as aldoiic addition of aldehydes (Henry reaction). Man-nich reaction, Michael addition, Diels - Alder reaction, for example (I55. ... 

Michael condensations, together with the Diels-Alder cycloaddition and the aldol reactions, are the most powerful and useful bond-fonning reactions in synthetic organic chemistry. Like the nitro-aldol (Henry) additions, nitroalkanes are particularly appropriate reagents in Michael reactions they act as a-hydrogen donors. Nitroalkanes react easily with typical Michael acceptors such as a,p-unsaturated aldehydes or ketones under base or Lewis acid catalysis. ... 

Jenner has investigated the effect of kinetic pressure on some nitro Michael and Henry reactions and has concluded that, although the kinetic effect is less than that reported for [4 -I- 2] cycloadditions, high pressure is a valuable tool... 

On the other hand, there is a report regarding a cascade Michael reaction followed by intramolecular nitro-Mannich (aza-Henry) reaction occurring between imides derived from diethyl aminomalonate and nitrostyrenes using thiourea 68a as catalyst (Scheme 7.63). This reaction results in a formal [3 + 2] cycloaddition between these two reagents, with this aminomalonate-derived... 

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. ... 

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