Nitromethane chalcones

Recently, the Texier-Boullet group [26] has prepared nitrocyclohexanols 10-77 by a twofold Michael addition/aldol reaction sequence (Scheme 10.19). Simply mixing chalcone 10-75 with nitromethane in the presence of a mixture of KF and A1203 under microwave irradiation gave 10-79 via the proposed intermediates 10-76, 10-77 and 10-78 as a single diastereomer in 65 % yield. One possible explanation for the stereoselectivity of the transformation is fixation of the reactive species onto the solid KF/A1203, as depicted in 10-79. 

Matsumoto and coworkers have introduced a new strategy for asymmetric induction under high pressure. The Michael addition of nitromethane to chalcone is performed at 10 kbar in the presence of a catalytic amount of chiral alkaloids. The extent of asymmetric induction reaches up to 50% ee with quinidine in toluene.201... 

Heterobimetallic asymmetric complexes contain both Bronsted basic and Lewis acidic functionalities. These complexes have been developed by Shibasaki and coworkers and have proved to be highly efficient catalysts for many types of asymmetric reactions, including catalytic asymmetric nitro-aldol reaction (see Section 3.3) and Michael reaction. They have reported that the multifunctional catalyst (f )-LPB [LaK3tris(f )-binaphthoxide] controls the Michael addition of nitromethane to chalcones with >95% ee (Eq. 4.140).205... 

The addition of nitromethane to chalcones has been studied using N-benzylquininium chloride as the chiral phase-transfer catalyst and fluoride ion as the base (46). The enantiomeric excess was moderate (up to 26%). No conclusions were drawn from this study. 

Sods [80] reported novel thiourea catalyst 134 in an efficient Michael reaction between nitromethane and chalcones to access chiral nitrocarbonyls in high enan-tioselectivity (Scheme 30). 

Figure 6.39 Cinchona alkaloid-thioureas prepared from quinine (121), dihydroquinine (122), C9-epi-quinine (123), and quinidine (124) catalytic efficiency evaluated in the Michael addition of nitromethane to tram-chalcone 1,3-diphenyl-propenone at 10mol% loading and rt.

Scheme 6.119 Michael adducts from the asymmetric addition of nitromethane to trans-chalcones catalyzed by 122.

Shibasaki made several improvements in the asymmetric Michael addition reaction using the previously developed BINOL-based (R)-ALB, (R)-6, and (R)-LPB, (R)-7 [1]. The former is prepared from (R)-BINOL, diisobutylaluminum hydride, and butyllithium, while the latter is from (R)-BINOL, La(Oz -Pr)3, and potassium f-butoxide. Only 0.1 mol % of (R)-6 and 0.09 mol % of potassium f-butoxide were needed to catalyze the addition of dimethyl malonate to 2-cy-clohexenone on a kilogram scale in >99% ee, when 4-A molecular sieves were added [15,16]. (R)-6 in the presence of sodium f-butoxide catalyzes the asymmetric 1,4-addition of the Horner-Wadsworth-Emmons reagent [17]. (R)-7 catalyzes the addition of nitromethane to chalcone [18]. Feringa prepared another aluminum complex from BINOL and lithium aluminum hydride and used this in the addition of nitroacetate to methyl vinyl ketone [19]. Later, Shibasaki developed a linked lanthanum reagent (R,R)-8 for the same asymmetric addition, in which two BINOLs were connected at the 3-positions with a 2-oxapropylene... 

Other nucleophiles such as nitromethane can also be used for this reaction. Thus, by the catalysis of (fl)-LPB (LaK3tris((/ )-binaphthoxide) (20 mol %), in which La works as a Lewis acid and K-naphthoxide works as a Brpnsted base, nitromethane reacted with chalcone to give the Michael adduct in 85% yield and 93% ee (Scheme 8D.8) [22], Addition of BuOH (120 mol %) gave a beneficial effect on the reactivity as well as the enantioselectivity of this reaction. 

Since Corey s group first reported 0(9)-allyl-N-(9-anthracenylmethyl) cinchonidi-nium bromide as a new phase-transfer catalyst [13], its application to various asymmetric reactions has been investigated. In particular, this catalyst represents a powerful tool in various conjugated additions using chalcone derivatives (Scheme 3.2). For example, nitromethane [14], acetophenone [15], and silyl eno-lates [16] produce the corresponding adducts in high enantioselectivity. When p-alkyl substrates are used under PTC conditions, asymmetric dimerization triggered by the abstraction of a y-proton proceeds smoothly, with up to 98% ee [17]. 

In 1978, Wynberg and coworkers reported the first example of a chiral quaternary ammonium fluoride-catalyzed Michael addition of nitromethane to chalcone (Scheme 9.1) [3]. The reaction was performed in toluene at 20 °C with 10mol% of chiral ammonium salt 1 or 3a and excess potassium fluoride (KF, 15 equiv.), yielding the y-nitro ketone with 10-23% enantiomeric excess (ee). The requisite chiral... 

Michael addition of nitromethane to chalcones can be catalysed by cinchona alkaloid-derived chiral bifunctional thiourea (142) (0.5-10 mol%) to give the corresponding products at 25-100 °C in high chemical yields and high enantioselectivity ... 

Scheme 6.2 Thiourea-catalyzed Michael additions of nitromethane to chalcones.

The use of numerous polymer-supported optically active phase transfer catalysts was further extended by Kelly and Sherrington11351 in a range of phase transfer reactions including a variety of displacement reactions, such as sodium borohydride reductions of prochiral ketones, epoxidation of chalcone, addition of nitromethane to chalcone and the addition of thiophenol to cyclohexanone. Except in the chalcone epoxidation, all the examined resin catalysts proved to be very effective. However, with none of the chiral catalyst system examined was any significant ee achieved. The absence of chiral induction is a matter of debate, in particular over the possible reversibility of a step and the minimal interaction within an ion pair capable of acting as chiral entities in the transition state and/or the possible degradation of catalysts and leaching. 

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). ... 

Later on, the substrate scope of this methodology was extensively explored by Corey s group using the structural analogues 23 and 24 of the above-discussed catalyst 16. A range of Michael donors such as nitromethane [9b] and silyl enolethers [9c] were successfully applied using the catalyst 23 or 24 (Scheme 9.9). In the case where the P-alkyl chalcones 25 with a proton at C(y) were used as acceptors, self-dimerization occurred under PTC conditions to produce the chiral 1,5-dicarbonyl... 

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 )... 

In contrast to the above prochiral donor reactions, only a limited number of prochiral acceptor reactions have been reported (Scheme 3) [13]. Nitromethane did not add to chalcone (13) in the presence of 1 in aprotic solvents. Although... 

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. 

A detailed study of this dehydrogenative condensation in the presence of triphenylmethyl perchlorate or fluoroborate was made by Simalty-Siemiatycki and Fugnitto. The reaction is best carried out in refluxing acetic acid nitromethane or acetonitrile give less satisfactory results. Chalcone reacts in these conditions with phenylacet-aldehyde yielding 2,4-diphenylpyrylium with an unsubstituted a-position. This and similar 2-unsubstituted pyrylium salts prepared by this method are so reactive that they do not afford pyridines on treatment with ammonia in the usual conditions this behavior is similar to that of the unsubstituted pyrylium perchlorate. The reaction of... 

Asymmetric Michael addition. Michael addition of nitromethane to chalcone (equation I) in the presence of a chiral amine (quinine, N-methylephedrine) proceeds in methanol (but not in aprotic solvents) in 60-807) yield, but the optical yield at best is 17>. However, if these amines are converted into aminium fluorides, the addition takes place in aprotic solvents (CaHsCHg, CH3CN) in 50-100% yield of more interest, asymmetric inductions of 207, can be obtained. (- )-BenzyIquininium fluoride (1) is particularly effective. The hydroxyl group in these salts is believed to play an important role in the stereochemical outcome of the reaction. Moreover, the fluoride ion is important as a strong base. 

Scheme 5.7 Enantioselective Michael reaction of nitromethane to chalcones applied to the enantioselective synthesis of baclofen.

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. 

TABLE 5.6. Effect of Ligand on the AM Reaction Between Chalcone and Nitromethane Catalyzed by NAP-MgO at 25 °C... 

The reduction of prochiral and/or sterically hindered ketones with and ammonium cations 40a, b derived from ephedrine afforded optically active alcohols in optical yields up to 13.7% the Edition of nitromethane to chalcone in the presence of KF occurs with an enantiomeric excess up to 26.2% . In the case of the reduction of ketones, the asymmetric induction dropped to values very close to zero for substrates lacking appreciable steric hindrance near the carbonyl group such as 2-octanone, acetophenone or propiophenone (Eq. (30)). 

Scheme 19.24 As mimetric addition of nitromethane to trans-chalcones utilising Cinchona-thiourea 17 as catalyst.

In 2005, Sons and coworkers introduced a novel bifunctional thiourea organocatalyst based on a Cinchona alkaloid for the asymmetric conjugate addition of nitromethane to tra s-chalcones. Using 10 mol% of thiourea 17, various electron-rich and electron-poor chalcones were well tolerated providing the desired adducts in high yields (80-94%) and very high enan-tioselectivities (95-96%) (Scheme 19.24). It has to be highlighted that... 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

An interesting example is the solvent-free Michael addition reaction of nitromethane to chalcone in the presence of alumina under microwave irradiation condition that gives the adduct in 90% yield (Scheme 91). ... 

Potassium fluoride, solubilized in acetonitrile with the aid of 18-crown-6, was found to catalyze the Michael addition of several carbon acids to a,/3-unsaturated nitriles or ketones. Nitromethane, for example, adds in 94% yield to chalcone under these conditions. 

A niamber of reactions have been examined using these phase transfer catalytic species. These include displacement reactions of solid potassium phenoxide, solid sodium azide and aqueous sodium azide on racemic ethyl-2-bromopropionate in toluene (similar to reaction 5), sodium borohydride (solid) reductions of acetophenone and octan-2-one, chalcone epoxidations using aqueous H2O2/OH" (reaction 4) and Michael additions of nitromethane to chalcone in the presence of anhydrous potassium fluoride (reaction 3). Details of these results will be published in due course and at the moment it is possible to record only a few representative examples of the displacements and reductions. 

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