Nitroalkenes stabilization

A second important reaction type considered in this chapter is conjugate addition, which involves addition of nucleophiles to electrophilic double or triple bonds. A crucial requirement for this reaction is an electron-withdrawing group (EWG) that can stabilize the negative charge on the intermediate. We focus on reactions between enolates and a,(3-unsaturated carbonyl compounds and other electrophilic alkenes such as nitroalkenes. 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

The formation of nitrocyclobutanes (44) is attributed to the contribution of the structure B" to the reactivity of stabilized zwitterionic intermediate B. The contribution of C-alkylation decreases due to steric hindrance caused by the presence of substituents at the a-position of the initial nitroalkene (42). 

Several nitroalkenes show high reactivity and/or low stability, individually indexed... 

In an analogous manner, nitroalkenes can be utilized as the electrophile in a tandem coupling-cyclization process (Eq. 2.18). Addition of a stabilized sulfonium ylide such as 209, to a variety of nitroalkenes provides an intermediate nitronic acid, which upon displacement of dimethyl sulfide provides a mixture of the corresponding nitrocyclopropane (XL) and cyclic nitronate (XLI). The ratio of products is highly dependent on the structure of the nitroalkene. For example, without a substituent on the a-position of the nitroalkene (R = H), only the... 

Schlessinger has shown that the addition of ester enolates to sulfur stabilized acceptors, e.g. ketene di-thioacetal monoxide (151) and methyl a-(methylthio)acrylate (187), is highly efficient for the synthesis of Y-ketoesters.148 Similarly, Ahlbrecht and Seebach have reported that amide and ester enolate additions to nitrogen stabilized acceptors, e.g. nitroalkenes (40) and 2-(/V-methylanilino)acrylonitrile (59 Scheme 72), are highly efficient.149... 

DMAP Catalysis to Form Key Substructures. DMAP has been used as a catalyst in the Morita-Baylis-HiUinan (MBH) reaction. Conjugated nitroalkenes can be reacted with an amine base to form a zwitterionic species that can add to many types of ketones and aldehydes. Remarkably, only DMAP and imidazole were able to effectively catalyze this reaction, likely due to their small size and ability to stabilize the intermediate. In another example, a unique catalyst system involving 1 1 1 DMAP TMEDA Mgl2 (each in 10 mol %) allowed the MBH reaction to proceed in fairly high yields between aldehydes and a , -unsaturated ketones, esters, or a thioester. ... 

A re-examination of proline-catalysed enantioselective Michael addition of aldehydes (R CH2CH0) with fran -nitroalkenes (R CH=CHN02) has identified a cyclobutane intermediate (109) derived from the reactants and catalyst. In situ NMR was used to discover the presence of (109) and to And that it represents a parasitic or resting state, arising from the iminium nitronate zwitterionic intermediate, siphoning it out of the productive catalytic cycle. Detailed kinetic studies also shed light on the role of acid catalysts and stability of the cyclobutanes (109) towards water and 0 aldehyde. For a similar possibly parasitic intermediate (72), see section titled The 0 Henry (Nitroaldol) Reaction . 

The 3 + 2-cycloaddition reaction of azomethine ylides with c-deficient alkenes produced polysubstituted l- and D-unnatural prolines. Also, phosphoramidite-(7u(OTf)2 complexes catalyse the 1,3-dipolar cycloaddition reactions of azomethine ylides with nitroalkenes to yield exo-tetrasubstituted proline esters." The 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, from iV-alkyl-a-amino acids and aldehydes, with 3-substituted coumarins provides l-benzopyrano[3,4-c]pyrrolidines in good yields and high regio- and stereo-selectivity." The organocatalytic 1,3-dipolar cycloaddition of azomethine ylides, derived from azlactones, with methyleneindolinones produced spirooxindoles with high yields (up to 95%) and high diastereo- (93 7 dr) and enantioselectivity (98% ee). ... 

Conjugate addition of stabilized carbanions can also be carried out with high enantiocon-trol. David A. Evans of Harvard University has described (J. Am. Chem. Soc. 2007, 129, 11583) the Ni-catalyzed addition of malonate 15 to nitroalkenes such as 14. Claudio Palomo of the Universidad de Pais Vasco (Angew. Chem. Int. Ed. 2007, 46, 8431) and concurrently Yujito Hayashi of the Tokyo University of Science (Organic Lett. 2007, 9, 5307) have developed organocatalytic protocols for the addition of nitromethane 18 to unsaturated aldehydes such as 17. 

---