Nitroalkene Michael reaction

The direct aziridinadon of nitroalkanes has been repotted for the first dme. Treatment of nitroalkene with an excess of CaO and NsONHCO-.Et fNs =4-nitroben2enesulfonyl gives the ct-nitroaziridine in good yields fEq. 10.70. ° The reaction proceeds via aza-Michael reaction followed by a ring closure. 

Hoashi, Y., Yabuta, T., Takemoto, Y. (2004) Bifunctional Thiourea-Catalyzed Enantioselective Double Michael Reaction of y,5-Unsaturated fS-Ketoesterto Nitroalkene Asymmetric Synthesis of (—)-Epibatidine. Tetrahedron Letters, 45, 9185-9188. 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Professor Seebach and coworkers (96) used silyl enolate (203) containing an additional C,C double bond in the Michael reaction with a-nitroalkene (204) in the presence of chiral LA (Scheme 3.146). 

Scheme 6.116 Adducts of the 117-catalyzed Michael reaction between 5-aryl-l, 3-dioxolan-4-ones and various trans-P-nitroalkenes.

In the presence of thiourea catalyst 122, the authors converted various (hetero) aromatic and aliphatic trons-P-nitroalkenes with dimethyl malonate to the desired (S)-configured Michael adducts 1-8. The reaction occurred at low 122-loading (2-5 mol%) in toluene at -20 to 20 °C and furnished very good yields (88-95%) and ee values (75-99%) for the respective products (Scheme 6.120). The dependency of the catalytic efficiency and selectivity on both the presence of the (thio) urea functionality and the relative stereochemistry at the key stereogenic centers C8/C9 suggested bifunctional catalysis, that is, a quinuclidine-moiety-assisted generation of the deprotonated malonate nucleophile and its asymmetric addition to the (thio)urea-bound nitroalkene Michael acceptor [279]. 

Figure 6.61 Bifunctional hydrogen-bonding pyrrolidine-(thio)ureas utilized for Michael reactions of ketones with nitroalkenes.

Scheme 6.179 Product range of the 213-catalyzed Michael reaction of cyclohexanone with various nitroalkenes.

The Michael reactions [149-152] between cyclohexanone and trons-nitroalkenes were also explored by Xiao and co-workers utilizing bifunctional pyrrolidine-thiourea 213 and the pyrrolidine-thioureas 214-217 (Figure 6.61) [344]. The model Michael reaction between cyclohexanone and trons-nitrostyrene identified water as the best solvent and 217 to be the most efficient catalysts concerning the activity and asymmetric induction (90% yield 96% ee dr 98 2 in 12 h at 35 °C) in the presence of benzoic acid (10mol%) as additive. The optimized catalytic system allowed the formation of a broad spectrum of Michael adducts such as 1-6 resulting from... 

Since nitro groups are readily converted to carbonyls by various procedures,4142 nitroalkenes can serve as a-carbonyl cation equivalents in Michael reactions.43 For example, addition of the amide enolate (158 Scheme 22) to the nitroalkene (157) affords, in 60% yield, the Michael adduct (159), which can be con-... 

Diphenylprolinol silyl ethers (17) have been found to be efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. 

The conjugate system of the C-2 nitroalkenes should posses some interesting chemical reactivity and it should be an excellent Michael reaction acceptor with reactive nucleophiles. Moreover, the steric effect of the bulky 1,6-anhydro ring should be similar to that of levoglucosenone. As a consequence, nitroalkenes are excellent precursors for the stereoselective introduction of an additional sugar moiety at C-2 with subsequent additional functional group such as nitromethylene or its reduced/acetylated analog. Moreover, this unsaturated C-2 functionality additionally fixes the conformation of the system and most importantly sterically hinders the P-D-face of both enone molecules. 

The reactivity of the nitroalkenes has been tested in the reaction with 1-thiosugars via conventional Michael reactions catalyzed by triethylamine. In both cases the stereoselective 1,2 addition proceeds by exclusive formation of an exo-adduct via formation of an S-linkage from the less hindered face of the molecule. As expected, the shielding effect of the 1,6-anhydro bridge effectively prevents the formation of the 2-equatorial product, yielding only the 2-axial products with a new quaternary center at C-2. This provides a stable molecule, as no epimerization or p-elimination is observed during the reduction of the nitro group. 

Acceptor-substituted alkenes that are employed as substrates in Michael additions include a./l-unsaturated ketones (for example, see Figure 10.59), a,/3-unsaturated esters (Figure 10.60), and a,/3-unsaturatcd nitriles (Figure 10.61). The corresponding reaction products are bifunctional compounds with C=0 and/or C=N bonds in positions 1 and 5. Analogous reaction conditions allow Michael additions to vinyl sulfones or nitroalkenes. These reactions lead to sulfones and nitro compounds that carry a C=0 and/or a O N bond at the C4 carbon. 

The elimination step also occurs easily with nitro compounds and is difficult to prevent in reactions with aromatic aldehydes. Now you can see how the useful nitroalkene Michael acceptors in Chapter 23 were made. 

On the other hand, conjugated nitroalkenes are very useful electron-poor alkenes, prone to act as nucleophilic acceptor, mainly in the Michael reaction (Berestovitaskaya et al., 1994) or in the Diels-Alder cycloaddition (Denmark and Thorarensen, 1996). Moreover, the nitro group can be easily turned into a respectable array of functional groups such as its reduction to a primary amine, replacement with hydrogen (Ballini et al., 1983 Ono, 2001), conversion into a carbonyl (Nef reaction) (Ballini and Petrini, 2004), and transformation into other important functionalities such as nitrile, nitrile oxide, oximes, hydroxylamines, and thiols (Colvin et al., 1979). 

Nitro olefins are useful intermediates in organic synthesis. Conjugated nitroalkenes are excellent acceptors (Michael reaction and Diels-Alder cycloaddition) and the nitro group can be further transformed, in situ, into several reactive intermediates. 

General comments about the Michael reaction procedures are analogous to those developed in the aldol and Mannich reactions.For example, the O-TMS-protected diphenylprolinol compound 20 in cooperation with benzoic acid catalyses the asymmetric Michael addition of aldehydes to nitroalkenes, in a simple, practical and efficient procedure. Benzoic acid promotes the rapid formation of the enamine intermediate and the reaction takes place in the highly concentrated organic phase of the aqueous biphasic system. 

The reaction involves the amine-catalyzed conversion of an aldehyde into a nitroalkene by reaction with nitromethane followed by a transition-metal-catalyzed Michael addition of p-dicarbonyl compounds in the same reaction vessel. Typically, amine catalysts and nickel complexes are incompatible due to their tendency to chelate and to render each other inactive. However, microencapsulation of poly(ethyleneimine) (PEI) forms catalyst 140, which can successfully be used in tandem with the nickel-based catalyst 141 (Figure 3.6). 

Reactions of the lithium etiolate of cyclohexanone with E-l-nitroalkenes in the presence of chiral lithium amides have been studied by Seebach and co workers [558], and good diastereo- and enantioselectivities are obtained in a few cases. The tin enolate of TV-propionoyloxazolidinone 6.83 undergoes diastereo- and enan-tioselective Michael reactions when coordinated to chiral amine 2.13 (R = NH-l-Np) [682] (Figure 7.59). Similar reactions show low enantiomeric excesses (5 70%) however, some Michael additions catalyzed by chiral catalysts have shown high selectivities ( 7.16). 

The bifunctional thiourea catalyst 16 was developed by Takemoto and co-workers in 2003 [61, 62], The Michael reaction of diethyl malonate with nitroalkenes proceeded with excellent enantioselectivities (Equation 10.31). 

Aza-Henry reaction is rendered asymmetric by quaternary salts of Cinchona alkaloids. Addition reactions. Changing the 9-hydroxy group of Cinchona alkaloids to a 9-epiamino group not only is synthetically expedient, such products often show excellent catalytic activities in many asymmetric reactions. Those derived from dihydrocinchona alkaloids mediate Michael reactions to good results, including addition of indole to enones, and carbonyl compounds to nitroalkenes. Salt 4 has also been successfully employed in the alkenylation of t-butyl a-aryl-a-cyanoacetate. ... 

Other condensations. The tripeptide H-(/J)-Pro-Pro-Asp-NH2 proves highly efficient in catalyzing the Michael reaction of aldehydes with conjugated nitroalkenes. " ... 

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