Enones nitromethane

To broaden the scope of the AM reaction, NAP-MgO-DAC in THF was evaluated using various acychc enones, nitromethane and 2-nitropropane. Chalcones gave good to excellent yields and ee s (Table 5.7, entries 1-7). Conversely, no reaction was observed using aliphatic enones. 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

In recent years, there has been increased recognition that water is an attractive medium for organic reactions from the environmental point of view. The Michael addition of various nitroalkanes to conjugated enones can be performed in NaOH (0.025 M) and in the presence of cetyltrimethylammonium chloride (CTAC1) as cationic surfactant in the absence of organic solvents (Eq. 4.109).146 The Michael addition of nitromethane to methyl acrylate is carried out in water using NaOH as a base to give the mono adduct (Table 4.2).147... 

Barco and coworkers have reported a more elegant synthesis of the nitrocyclohexanone via the double Michael addition of nitromethane with enones. (Eq. 4.130).178... 

Conjugate addition of RN02 to enones. Primary nitroalkanes and a, (3-enones when activated by alumina form conjugate addition products that are oxidized in situ by alkaline hydrogen peroxide to 1,4-diketones. A similar reaction of nitromethane with a vinyl ketone provides 1,4,7-triketones. 

As with epoxides, carbanions can add in a 1,4 fashion to enones or nitrosugars. Nitromethane anion has been used [64], Dithiane anion has been successfully used in the addition to nitroolefins [65] and to enones [66], Accordingly, C-5 branched-chain glucose derivatives 47 and 48 have been prepared from nitroolefin 46 (Scheme 20) [67,68], Sugar-derived enones have been also used as acceptors in free radical reactions to trap alkyl radicals as well as anomeric radicals (see Schemes 29 and 30). 

The enantio-determining step of nucleophilic additions to a-bromo-a,y -unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [20]. The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an a-cyanosulfone [20]. 

Condensation of A-rerf-butoxycarbonylpelletierine (12) with benzaldehyde proceeded smoothly in aqueous methanolic sodium hydroxide to afford the enone 14 in 90% yield. Deprotection with either hydrogen chloride in nitromethane or trifluoroacetic acid in methylene chloride furnished 9 (Ar = C6H5), which had been considered as an intermediate in pathway a (Scheme 1). The cyclization of 9 (Ar = C6H5) in CDC13 without base, monitored by H-NMR, revealed that the reaction was completed after 3 days to give the cis isomer 15 as a sole product. None of the trans isomer 16 was formed under these conditions even after 2 weeks. 

Asymmetric Michael Addition of Nitromethane to Enone. N-Methylephedrinium fluoride catalyzes the Michael addition of nitromethane to chalcone to afford the adduct with 23% ee in 50% yield (eq 27). ... 

As described in Sections 2.3.1.2 and 2.2.3, Choudary et al. recently revealed nanocrystalline magnesium oxide (NAP-MgO) as a recyclable heterogeneous catalyst [40, 45]. These authors extended the use of this new type of heterogeneous catalyst for the asymmetric Michael reaction of different acyclic enones with nitromethane and 2-nitropropane [69a]. In a Michael reaction of chalcone with nitromethane in THF solvent at -20°C, NAP-MgO/(lR,2R)-(-)-diaminocyclohexane (DAC) was found to be an excellent catalyst system (96% ee, 95% yield) (Scheme 2.32). This Michael reaction proceeds via the dual activation of both substrates (nucleophiles and electrophiles) by NAP-MgO. The Lewis basic site (O /O ) of the NAP-MgO activates the nitroalkanes, while the Lewis acid moiety (Mg /Mg )... 

The enone 3 was further functionalized via tandem reaction by Michael addition of methanol to the conjugate system at C-5, followed by base catalyzed nitromethane addition to the keto function at C-2 and base catalyzed (TMG -tetramethylguanidine) mesylation/elimination with the formation of new a-nitroenone as depicted in Scheme 7. The intermediate a-nitroenone functionalized at C-2 as a conjugate system is indeed an excellent Michael acceptor of reactive nucleophiles, including 1-thio-P-D-glucose. The conjugate addition of this reactive thiol was performed in the same fashion as before (2, 3) with the stereoselective formation of the first representative example of highly functionalized and previously unknown class of C-nitro-5-thiodisaccharide derivatives. 

Scheme 11. Stereoselective functionalization of enone 3 via Michael addition of nitromethane/reduction and thiacetic acid/nitromethane reduction approach.

Noteworthy was the increase of the selectivity in water toward the 1 1 adduct when using nitromethane. Under slightly alkaline conditions, cetyltrimethylam-monium chloride was shown to catalyze the addition of various nitroalkanes onto conjugated enones [176]. Amines also reacted in aqueous Michael additions, especially with a, -unsaturated nitriles [177]. The lack of apparent reactivity of a, -unsaturated esters comes from the reverse reaction which is particularly accelerated in water. In these amine additions, water activation was compared with high pressure giving support to the implication of the hydrophobic effect. A related reaction is the Baylis-Hillman reaction which proceeds readily in water with a good rate enhancement (Scheme 34) [178]. 

The same method, using Co(acac)2 and the chiral diamines has also been applied to several other stabilized carbanions and enones with up to 100% yield, however, the asymmetric inductions did not exceed 40% ee59. Similarly, a catalyst derived from Ni(acac), and (+ )-(S)-2-(anili-nomethyl)pyrrolidine, (—)-(5)-prolinamide or (—)-(S)-prolinol catalyzes the conjugate addition of nitromethane to benzalacetone, chalcone and 2-cyclohexenone with up to 59% ee62,67. 

D-A reactions, comprising st-DNA and the Cn " complex of 4,4 -dimethyl bipyridine. Nitromethane and dimethyl malonate, both of which enolize readily, were employed as the nncleophiles. With 100 equivalents of dimethyl malonate, a clean and quantitative conversion into the Michael addnct was observed after 3 days, with an ee of 91%. The addition of nitromethane was slower nsing 1000 equivalents 97% conversion and an ee of 85% were obtained in the same time. The snbstrate scope proved to be broad a series of derivatives of the snbstrate were tested in the Michael reaction and generally gave high conversions (typically > 75%) and ees (86-99% with dimethylmalonate as the nncleophile, and 82-94% with nitromethane as the nncleophile). Only in the case of the Michael addition to the enone with R = Me instead of aryl, did the ee drop to 60%. Again, it was shown that the reaction conld be performed on a preparative scale (1 mmol), and that the catalyst solution conld be recycled withont loss of activity or enanti-oselectivity over at least two rnns. 

A highly enantioselective conjugate addition of nitromethane and nitroethane to acyclic enones has been recently achieved using chiral cyclohexanediamine-derived primary amine thiourea 48 (Scheme 2.57) [168], With respect to the electrophile, the reaction shows a broad substrate scope and not only 1-aryl- but also 1-alkyl enones afford the corresponding chiral y-nitroketones with good yields and excellent enantioselectivities (92-99% ee). 

The Michael addition of (phenylthio)nitromethane to a steroidal enone and nitro displacement (eq 12) has been employed in the stereoselective 16-methylation of corticosteroids. ... 

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