Carbon nucleophiles nitroalkenes

Nitro ilkenes are gener illy prepared by the subsdnidon reacdon of fi-nirro sulfides and sulfoxides with a variety of carbon nucleophiles via an addidon-eliminadon sequence. This method is partiadarly usefiil for the preparadon of cyclic nitroalkenes fEq. 4.100. ... 

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. 

Nitroalkenes with potential leaving groups in (3-position such as a dialkylamino, an alkylthio, or a phenylsulfonyl group undergo addition-elimination reactions with nucleophiles. The chemistry of nitroenamines has been extensively investigated, and their potential utility in organic synthesis has been well established.2613 116 Severin and coworkers have developed the addition of elimination reactions of nitroenamines with carbon nucleophiles in 1960-1970, as exemplified in Eq. 4.94.117... 

The first organocatalyzed conjugate addition of a-substituted p-ketoester to a,P-unsaturated ketones was presented by Deng et al. [42] (Scheme 3). Although traditional Cinchona alkaloids were efficient catalysts for conjugate addition of carbon nucleophiles to nitroalkenes and sulfones, replacement of the C(9)-OH with an ester group (Q-7b) showed great improvement in stereoselectivity. The reaction is applicable to a variety of cyclic and acyclic enones (16,18). 

The use of naphthols 145 as the carbon nucleophilic readion component in Friedel-Crafts type Michael addition readions was also reported in 2007 by Chen and coworkers [43], In this system, the pronucleophile is activated by the quinuclidine unit of bifundional cinchona-based thiourea catalysts such as 81a. A range of aryl-and alkyl-substituted nitroalkene derivatives 124 were applicable to this system. The corresponding adducts 146 were obtained with 85-95% ee at low temperature... 

The Michael addition reaction is commonly recognized as one of the most important carbon-carbon bond-forming reactions in organic synthesis, and major efforts have been made to develop efficient catalytic systems for this type of transformation. In particular, the Michael addition of a carbon nucleophile to nitroalkenes is a useful synthetic method for the preparation of nitroalkanes [76], which are versatile synthetic intermediates owing to the various possible easy transformations of the nitro group into other useful functional groups, such as amino groups and nitrile oxides. 

Shortly after, the same laboratory developed a highly enantioselective and diastereoselective catalytic conjugate addition of an exceptionally wide range of trisubstituted carbon nucleophiles (cyclic and acyclic p-ketoesters, 2-substituted 1,3-diketones, a-nitroesters and ot-cyanoesters) to nitroalkenes mediated by related CPN and CPD derivatives (Scheme 14.2). This simple methodology allowed the efficient synthesis of important building blocks containing adjacent quaternary and tertiary stereocentres. 

Two years later, the same authors studied the reactions previously developed by Deng and coworkers (Scheme 14.2) for the s)mthesis of quaternary and tertiary carbon centres through the Michael addition of trisubstituted carbon nucleophiles to nitroalkenes, performed under this new protocol (low loading NaCPN (1 mol%), in water, at room temperature). Yields and selectivities were moderate to excellent (41-92%, dr 2.5 1-12.9 1, ee 21-88%) and the protocol could be applied even on a large scale (0.8 mol). 

Scheme 14.2 Asymmetric Michael addition of trisubstituted carbon nucleophiles to nitroalkenes. Phn = 9-phenanthryl.

The importance of an -OH group at the C6 position for an organocatalytic reaction was noted by Deng and coworkers in a series of studies of C9 ether derivatives of cupreine and cupreidine [34]. Based on the observation that the C9 0-benzyl and O-phenanthryl ether derivatives (10 and 11, respectively. Figure 6.5) gave similar results for the conjugate addition of carbon nucleophiles to nitroalkenes as obtained with 3 (Scheme 6.18) [34], a transition state model was proposed for this reaction. 

Figure 6.6 Tentative model for the transition state of the catalytic conjugate addition of a carbon nucleophile to a nitroalkene with the cupreine derivative in a gauche open conformation [34],...

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. 

Nitroalkanols are intermediate compounds that are used extensively in many important syntheses 142). They can be converted by hydrogenation into / -aminoalcohols, which are intermediates for pharmacologically important chemicals such as chloroamphenicol and ephedrine. They are obtained by Henry s reaction by the condensation of nitroalkanes with aldehydes. The classical method for this transformation involves the use of bases such as alkali metal hydroxides, alkoxides, Ba(OH)2, amines, etc. 142-144). However, these catalysts give predominantly dehydrated products—nitroalkenes— which are susceptible to polymerization (Scheme 16). The reaction proceeds by the nucleophilic addition of the carbanion formed by the abstraction of a proton from the nitro compound to the carbon atom of the carbonyl group, finally forming the nitroaldol by abstraction of a proton from the catalyst. 

Nitroalkenes can serve as the two-carbon fragment of a [3 + 2] cyclization involving enamines as nucleophiles (equation 86) (81LA1534). This reaction is presumably initiated by a conjugate addition of the enamine to the nitroalkene (equation 87). The most attractive formulation of the cyclization is via an intramolecular nucleophilic addition to the aci-form of the nitronate anion. This provides a reduced nitrogen substituent which could be eliminated to complete aromatization. This procedure has provided quite satisfactory yields over a range of structural types. 

---