Michael addition to nitroalkenes

Nitroalkenes react with lithium dianions of carboxylic acids or with hthium enolates at -100 °C, and subsequent treatment of the Michael adducts with aqueous acid gives y-keto acids or esters in a one-pot operation, respectively (Eq. 4.52).66 The sequence of Michael addition to nitroalkenes and Nef reaction (Section 6.1) provides a useful tool for organic synthesis. For example, the addition of carbanions derived from sulfones to nitroalkenes followed by the Nef reaction and elimination of the sulfonyl group gives a,P-unsaturated ketones (Eq. 4.53).67... 

The chiral enamines provide the opportunity for the enantioselective Michael addition to nitroalkenes, as shown in Eq. 4.68, where the ketone is obtained as a single diastereomer with... 

Sequential Michael additions are versatile methods for the construction of cyclic compounds. Although a variety of these reactions have been developed, the use of alcohols as nucleophiles for the Michael addition to nitroalkenes has been little studied. Recently, Ikeda and coworkers have reported an elegant synthesis of octahydrobenzo[b]furans via the sequential Michael addition of 1-nitro-cyclohexene with methyl 4-hydroxy-2-butynoate in the presence of t-BuOK followed by radical denitration (Eq. 7.74).94... 

The Michael addition to nitroalkenes followed by cyclization provides a general method for the synthesis of various pyrroles. The reaction of nitroalkenes with acetoacetate followed by reduction with Zn in acetic acid provides another route to 2-methyl-3-pyrrolecarboxylates (Eq. 10.8).10... 

The bis-prolinol-derived phenol (156) has been designed to facilitate the formation of heterodinuclear complexes based upon the large difference in pKH of the phenolic OH group and the tertiary OH groups. The first examples of its application involve hydroxyacetophenones (157) as donors in the asymmetric Michael addition to nitroalkene acceptors (158) the best stereocontrol was observed with a zinc- magnesium dinuclear complex, where enantiomeric excesses ranged up to 92% for the major anti diastereoisomer (159).212... 

SMP enamines have a very broad range of applications as d synthons. Cyclohexanone SMP enamine can be used for efficient Michael additions to nitroalkenes, Knoevenagel acceptors, and to a nitroallylic ester in a [3 + 3] carbocyclization with excellent stereoselectivities (eq 1). The synthesis of y-oxo-a-amino acids using SMP enamines has been developed (eq 2). ... 

Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphon-ates (281), a new class of chiral iminodienophiles, and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts (282). Hydrogenation of (282) results in a ring opening that affords the first examples of optically pure quaternary piperidine phosphonates. Two step synthesis of an enantiomeric pure cyclic phosphite (283) and its application as a chiral phosphorus nucleophile in the asymmetric Michael addition to nitroalkenes (284) provides an efficient... 

Varying diastereoselections are achieved with proto nations following Michael additions to nitroalkenes whereby improvement by the above de-/reprotonation should be possible. 

Scheme 2.32 Enantioselective Michael addition to nitroalkenes catalysed by quinine-derived chiral sodium(i) salt.

Similar Henry-type condensations were utilised in syntheses of heterocyclic derivatives from o-hydroxy-benzaldehydes. Condensations with bromonitromethane afforded 2-nitrobenzoC ]furans after dehydration of intermediate nitroaldols in refluxing acetic anhydride,whilst Michael additions to nitroalkenes prior to... 

The proposed sequence begins with the condensation between the catalyst (S)-70 and the acrolein 131 to give the iminium intermediate A, which selectively reacts with the hard oxygen nucleophile 169, to afford the enantine intermediate B. The preferred Michael addition to nitroalkene 140 furnishes C, which in the third step reacts with a second equivalent of A to generate the unstable enamine D, which under a fast intramolecular aldol condensation yields the wanted product 170. 

Acetylazaarenes ArCOMe undergo Michael addition to nitroalkenes in the presence of the Ni(II) complex (399) as a Lewis acidic catalyst, giving rise, for example, to (400) in FVCH at r.t. with 65-99%... 

B.M. Trost, J. Hitce, Direct asymmetric Michael addition to nitroalkenes vinylogous nudeophiUcity under dinudear zinc catalysis, J. Am. Chem. Soc. 131 (2009) 4572-4573. 

Racemic cx-fluoro-p-ketophosphonates (549) have been used in stereoselective Michael addition to nitroalkenes (550) promoted by the trifunctional thiourea organocatalyst (552). The reaction afforded highly functionalised a-fluoro-p-keto-y-nitrophosphonates (551) in high yields (up to 99%) and with excellent stereochemical control (96-99% ee and 3 1-34 1 d.r.) (Scheme 159). ... 

Under the catalysis of 22c, a structurally similar pro-nucleophile, a-tert-butylthio-substituted furanone, underwent the highly syn- and enantioselective vinylogous Michael addition to nitroalkenes (Scheme 7.38) [62). These methods allowed fadle access to optically active polyfunctionaUzed butenolides, which are versatile chiral synthons in organic synthesis. 

Figure 10.4 Squaramide catalysts used for Michael additions to nitroalkenes.

Enantioselective Friedel-Crafts reactions using metal-based chiral catalysts or chiral organocatalysts have been investigated extensively because the reactions directly provide alkylated arenes, a pharmacologically important substructure, in optically active forms. The chiral phosphoric acid catalyzed Friedel-Crafts reaction was first accomplished via the activation of imines but, currently, the scope of the electrophilic components has been broadened to include the Michael addition to nitroalkenes, a, 3-unsaturated carbonyl compounds, and so on. 

In parallel, Xu and coworkers discovered that in the presence of similar I L-tagged pyrrolidines 84c,d the reaction proceeded nearly as efficiently in the [bmimJIPFs] medium, so there is no need to dehver the acid co-catalyst (TFA) to the system because this role is obviously played by the IL fragment [96]. Catalysts 84a,b were recovered from the reactant medium by precipitation with ether, while the 84c,d/ IL systems were reused after product extraction without further purification. Four reaction cycles of catalysts 84 did not reduce reaction diastereo- and enantioselec-tivities however, the recovered catalysts gradually became less active with each cycle. Surfactant-type IL-supported asymmetric organocatalyst 84e synthesized by Luo and Cheng and coworkers in 2006 catalyzed Michael addition to nitroalkenes with high stereoselectivities in water without any additives [97]. 

Recently, Takemoto s catalyst 27 was also employed in the addition of P-ketoamides [34] with excellent results. Bonne, Constantieux, Rodriguez et cA. [35] reported the use of a-ketoamides as pronucleophiles in the Michael addition to nitroalkenes catalyzed by the bifunctional Takemoto s aminothiourea 27. During this study it appeared that the nature of the amide moiety was crucial, indeed tertiary amides were poorly reactive during conjugate addition while secondary amides gave excellent results in terms of yields (67-94%), enantioselectivity (99% > ee > 85%), and diastereoselectivity (20 1 > dr > 10 1) (Scheme 34.7). The authors... 

Among the few examples of pure acidic activation in Michael addition to nitroalkenes, the recent works of Ooi and coworkers described the aza-Michael addition of aniline [50] by the charged chiral C2 symmetric phosphonium 50 (Scheme 34.16). Indeed, the acidic spirocycUc catalyst 50 was able to asymmetrically activate a Lewis base such as 2,4-dimethoxyaniline, to promote the addition to nitroolefins with excellent yields and selectivity. 

The simplest enoUzable aldehyde, acetaldehyde, was until recently not examined in organocatalytic reactions due to its high reactivity as electrophile or as nucleophile leading to intractable mixture of products resulting from side reactions. The groups of List [63] and Hayashi [64] reported independently the use of acetaldehyde as donor in Michael addition to nitroalkenes (Scheme 34.24). They both selected diphenylprolinol silyl ether (6) as the best catalyst but employed different solvents (acetonitrile or DMF/Pr OH for LisL and 1,4-dioxane for Hayashi) at room temperature. Similar selectivities were observed under both conditions but higher yields were obtained with Hayashi s conditions. 

Azaarylacetates and acetamides, such as (399), have been reported to undergo Michael additions to nitroalkenes (394) in the presence of the nickel(II)-bis(diamine) complex 0 (401) and molecular sieves to produce (400) with >19 dr and <99% ee 0... 

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