Michael acceptors nitroalkenes

Chen and co-workers presented, in 2007, a Michael-type Friedel-Crafts reaction of 2-naphthols and trans-P-nitroalkenes utilizing the bifunctional activating mode of cinchonine-derived catalyst 117 [277]. The nitroalkene was activated and steri-cally orientated by double hydrogen bonding, while the tertiary amino group interacts with the naphthol hydroxy group to activate the naphthol for the nucleophilic P-attack at the Michael acceptor nitroalkene (Scheme 6.117). 

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

Dehydration of fi-nitro iilcohols provides an important method for the preparation of nitroalkenes. Because lower nitroalkenes such as nitroethylene, Tnitro-Tpropene, and 3-nitro- Tpropene tend to polymerize, they must be prepared careftdly and used immediately after preparation. Dehydration v/ith phthalic anhydride is the most reliable method for such lower nitroiilkenes. Such lower nitroalkenes have been used as important reagents for Michael acceptors or dienophiles in the Diels-Alder reacdon, which v/ill be... 

Nitroalkenes are shown to be effective Michael acceptor B units In three sequential re fA + B + C couplingi in one reaction vessel. The sequence is initialed by enolate nucleophiles fA and is terminated by aldehydes or acrylate electrophiles fC. The utility of this protocol is for rapid assembly of complex stnictures from simple and readily available components. A short total synthesis of a pyrroLmdine alkaloid is presented in Scheme 10.16. ... 

Nitroalkenes are also reactive Michael acceptors under Lewis acid-catalyzed conditions. Titanium tetrachloride or stannic tetrachloride can induce addition of silyl enol ethers. The initial adduct is trapped in a cyclic form by trimethylsilylation.316 Hydrolysis of this intermediate regenerates the carbonyl group and also converts the ad-nitro group to a carbonyl.317... 

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. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the direct nucleophilic addition of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols <06JA4932>. In the presence of a fluoride anion, carbinol 186 is not cleaved to an aldehyde... 

The stereochemical trends discussed above are not limited to a, yS-unsaturated carbonyl compounds other Michael acceptors such as nitroalkenes and unsaturated phosphane oxides display similar behavior. A representative example for the nitroalkene class of Michael acceptors is shown with substrate 70 in Scheme 6.13 [28]. The best results were thus obtained for arylcuprates. Other organocuprates were much less selective, which severely restricts their application in organic synthesis. 

Nitroalkenes are excellent Michael acceptors, and asymmetric 1,4-additions to nitroalkenes (Scheme 7.22) provide access to highly versatile synthons, since the nitro group is readily reduced to the corresponding amine [74]. Seebach, employing a... 

When nitroalkenes were used as Michael acceptors, high yields and enantioselectivities of the desired Michael addition products were also obtained (Scheme 5.22). In these reactions, a well-defined chiral Ru amido complex (Figure 5.9) was an efficient catalyst. The mild reaction conditions and high reactivities and stereoselectivities allowed a large-scale reaction in the presence 1 mol% Ru catalyst. By using a chiral Pd(II) catalyst, an asymmetric allylic arylation was reported by Mikami and coworkers to give the cross-couphng product via the activation of both allylic C H and aryl C H bonds in moderate enantioselectivity (Scheme 5.23). ... 

Mobashery and co-workers also reported the synthesis and inhibitory apph-cation of 2 -N02 derivatives of neamine and kanamycin (Scheme 4.28). Using the metal-chelating method, the 2 -NH2 was selectively unmasked and then oxidized into 2 -N02, which will increase the acidity of 2 -H. Upon phosphorylation at the 3 -0H, elimination of phosphate will lead to the formation of a nitroalkene intermediate, 198, that can function as a Michael acceptor and... 

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]. 

The conjugate addition of phosphorus nucleophiles of various oxidation states and in neutral or metallated form constitutes an efficient and well-known method for C—P bond formation [30]. In the case of phosphanes as nucleophiles especially, the corresponding phosphane-borane adducts have been used in 1,4-additions to Michael acceptors. Following the idea to use a chirally modified phosphorus nucleophile in asymmetric Michael additions to aromatic nitroalkenes, we synthesized the new enantiopure phospite 45 starting from TADDOL (44) with nearly quantitative yield. Due to the C2 symmetry, of the... 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

As a consequence of the strong electron-withdrawing properties of the nitro group, conjugated nitroalkenes behave as powerful Michael acceptors. An example of conjugate addition of Reformatsky reagents to (2-nitrovinyl)arenes 107 is given in equation 63150. 

Thiamine-catalyzed transformations are reversible, thus TV,/V-dialkyl hydrazones were selected as alternative acyl anion equivalents that were reported to react with electrophiles without acidic activation.41 One especially reactive example, formaldehyde hydrazone resin 13, was constructed from polymer-supported hydrazines and was employed in the first polymer-supported, uncatalyzed acyl anion additions (Fig. 8).38 As test substrates, nitroalkenes (as Michael acceptors) and activated aldehydes were selected. Reactivity of these acyl anion equivalents depended critically not only on the nature of the starting hydrazine, but also on the protocol for hydrazine formation. 

Further applications of the chiral ammonium bifluoride-catalyzed enantioselective Michael addition of silyl nitronates has been shown in the reactions with nitroalkenes as a Michael acceptor (Scheme 9.17). These studies were started by examining the reaction of nitropropane-derived silyl nitronate 23b with P-nitrostyrene, using the chiral quaternary ammonium bifluoride (R,.R)-6d. When P-nitrostyrene was treated with 23b (1.2 equiv.) in the presence of (K,f )-6d (2mol%) in THF at — 78 °C, the... 

The relative Michael-acceptor abilities of a variety of substituted aromatic and aliphatic nitroalkenes have been elucidated by computational methods. Several global and local reactivity indices were evaluated with the incorporation of the natural charge obtained from natural bond orbital (NBO) analysis. Natural charges at the carbon atom to the NO2 group and the condensed Fukui functions derived by this method were found to be consistent with the reactivity.187... 

One-pot system starting from parent ketones, sec-Buhi, Bu3SnBr, and Michael acceptor is accomplished for various types of substrates.233 The reaction of tin enolates with nitroalkenes is effectively catalyzed by Bu4NBr to give 7-nitroketones. The catalyzed reaction provides higher yield and selectivity as compared with the uncatalyzed... 

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. 

Nitroalkenes, vinyl sulfones and vinylphosphonium salts have been shown as good Michael acceptors for 2-lithio-l,3-dithiane derivatives. Nitroalkene sugar derivative 246 has been used as electrophile for the synthesis of branched-chain cyclitols397 - 399. Seebach and Langer studied the addition to simple nitroalkenes using the chiral solvent (,S ,.S )-DDB (247) with some degree of diastereoselectivity400,401. 

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