Enones nitroalkane addition

Conjugate addition of nitroalkanes to enones, This addition can be effected with basic alumina in the absence of a solvent at 25° in 50-88% yield. 

These reports triggered a considerable exploration and exploitation of Cinchona amine catalysts for a variety of enamine and iminium ion mediated reactions. Regarding C-C bond formation through a conjugate addition reaction, it is worth mentioning two examples of 1,4-additions to enones the addition of coumarins and related derivatives, developed by Chen and coworkers, which leads to pharmaceutically relevant compounds such as warfarin, and the synthetically important addition of nitroalkanes to the same Michael acceptors, reported more recently by Wang, Duan and coworkers (Scheme 14.8). ... 

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... 

The Michael addition of nitroalkanes to a,P-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a h Various natural products have been prepared via this route.157 For example, r/.v-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f... 

The synthesis of 2,3,5-trialkylpyrroles can be easily achieved by conjugate addition of nitroalkanes to 2-alken-l,4-dione (prepared by oxidative cleavage of 2,5-dialkylfuran) with DBU in acetonitrile, followed by chemoselective hydrogenation (10% Pd/C as catalyst) of the C-C- double bond of the enones obtained by elimination of HN02 from the Michael adduct. The Paal-Knorr reaction (Chapter 10) gives 2,3,5-trialkylpyrroles (Eq. 4.124).171... 

Catalytic enantioselective nucleophilic addition of nitroalkanes to electron-deficient alke-nes is a challenging area in organic synthesis. The use of cinchona alkaloids as chiral catalysts has been studied for many years. Asymmetric induction in the Michael addition of nitroalkanes to enones has been carried out with various chiral bases. Wynberg and coworkers have used various alkaloids and their derivatives, but the enantiomeric excess (ee) is generally low (up to 20%).199 The Michael addition of methyl vinyl ketone to 2-nitrocycloalkanes catalyzed by the cinchona alkaloid cinchonine affords adducts in high yields in up to 60% ee (Eq. 4.137).200... 

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (25)-L-prolines are used, acyclic ( )-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessianhas reported that L-proline (3 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloal-kanones.204... 

The Nef reaction can also be carried out with reducing agents. Aqueous titanium chloride reduces nitro compounds to imines, which are readily hydrolyzed to carbonyl compounds (Eq. 6.17).28 The Michael addition of nitroalkanes to enones followed by reaction with TiCl3 provides an excellent route to 1,4-diketones and hence to cyclopentenones. For example, cw-jasmone is readily obtained,28 as shown in Eq. 6.18. 

Elegant application of the Michael addition of nitroalkanes to enones followed by denitration is demonstrated in the synthesis of (+) dihydromevinol, (see Scheme 7.9).75... 

Alternatively, Ballini devised a new strategy to synthesize tri-alkylated pyrroles from 2,5-dialkylfurans and nitroalkanes <00SL391>. This method involves initial oxidation of 2,5-dimethylfuran with magnesium monoperoxyphthalate to cA-3-hexen-2,5-dione (6). Conjugate addition of the nitronate anion derived from the nitro compound 7 to 6 followed by chemoselective hydrogenation of the C-C double bond of the resulting enones 8 (obtained by elimination of nitrous acid from the Michael adduct) completes the conversion to the alkylated y-diketones 9. Final cyclization to pyrroles 10 featured improved Paal-Knorr reaction conditions involving reaction of the diketones with primary amines in a bed of basic alumina in the absence of solvent. 

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. 

A stereocontrolled synthesis of racemic monomorine I (16a) has been accomplished by Stevens and Lee (438). An allyl alcohol obtained by reaction of acrolein with the Grignard reagent of the chloroacetal (367) was oxidized to yield the enone (368). The Michael addition of 1-nitropentane to 368 was catalyzed by tetramethylguanidine to yield the nitroalkane (369). Reductive cyclization of 369... 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

Nitroketones are reduced to pyrroles by diphenyl disulfide and triphenylphosphine (86JCS(Pl)2243). Since 7-nitroketones are accessible by Michael additions of nitroalkanes to enones, this is a potentially versatile method (Scheme 40). 

Use of proline as a catalyst has become an important methodology in the catalytic asymmetric addition of stabilized carbanions to conjugated carbonyl compounds. Hannessian employed L-proline (S)-l in the addition of nitroalkanes to enones (Scheme 1) [5]. In the presence of 3-7 mol % of (S)-l and an excess of trans-2,5-dimethylpiperazine in chloroform, comparable or higher enantiose-lectivities were attained compared to the Yamaguchi s method using L-proline... 

A rubidium salt of proline (5-10 mol%) has been reported to catalyse the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When L-proline was used, acyclic (I )-enones produced (.S )-adducts. whereas cyclic (Z)-enones gave (R )-adducts.88... 

Nef transformation,3 A versatile route to 1,4-diketones involves Michael addition of a nitroalkane to an a,/J-enone, which can be effected in 80% yield when catalyzed by fluoride ion (9, 446-447). The resulting y-nitro ketone is oxidized efficiently by a stoichiometric amount of KMn04 impregnated on silica gel to a 1,4-... 

Pyrrolidin-2-yltetrazole has been found to be a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones.45 Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species. 

Yamaguchi et al. also showed that Rb-L-prolinate catalyzes enantioselective addition of nitroalkanes to several acyclic and cyclic enones [25, 26]. For acyclic enone acceptors the best result, i.e. 74% yield and 68% ee of the S product, was achieved in the addition of 2-nitropropane to -3-penten-2-one (40a, Scheme 4.13) [25]. Screening of several proline derivatives and cyclic amino acids of other ring size resulted in the identification of the O-TBDMS-derivative of 4-hydroxyproline as the best catalyst for addition of nitrocyclohexane to cycloheptenone. In this particular reaction 74% yield and 86% ee were achieved [26]. 

The proline-catalyzed conjugate addition of nitroalkanes was further developed by Hanessian and Pham, resulting in enantiomeric excesses up to 93% in the addition of a variety of nitroalkanes to cyclic enones (Scheme 4.14) [27]. In their catalytic system, L-proline (3-7 mol%) was employed together with equimolar amounts (relative to the substrate enones) of trans-2,5-dimethylpiperazine. The latter addi-... 

The Michael addition of nitroalkanes to a,B-unsaturated enones catalyze0 "y... 

The Michael addition of nitroalkanes to a,f -unsaturated enones, catalysed by the novel chiral imidazolidine-2-yltetrazole (151), has been investigated. The new, more soluble organocatalyst decreases reaction times and improves enantioselectivities com- pared with other catalysts. The Michael addition adducts were obtained with up to 92% ee.179... 

General Procedure for Conjugate Addition of Nitroalkanes to a,) -Unsaturated Enones [26a-c] (p. 109)... 

Halland N, Hazell RG, Jprgensen KA (2002) Organocatalytic asymmetric conjugate addition of nitroalkanes to alpha,beta-unsaturated enones using novel imidazoline catalysts. J Qrg Chem 67 8331-8338... 

In 2008, Ye and coworkers also developed a new type of multifunctional cinch-onidine-based catalyst, such as 119 having an additional primary amine moiety, for the Michael addition of nitroalkane to cydic enones [32], In the presence of an acid cocatalyst, the primary amine moiety of 119 can act as a Lewis base to activate the Michael acceptor via iminium formation. The catalysts 119a and 119b (5 mol%) provided quite excellent enantioselectivity (up to 98% ee) for the Michael addition of nitroalkanes to cyclohexenone (Scheme 9.40). The observed retardation of the reaction rate and the opposite sense of enantioselectivity obtained with the catalyst 119b indicated the importance of the configuration of the cydohexane... 

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]. 

Nitroalkanes can be added to the enone moiety of enaminones to give, e.g., nitroalkyl-substituted cyclohexanone derivatives by a base-catalysed Michael addition (equation 236). 

A huge acceleration of the Michael reaction of nitroalkanes with methyl vinyl ketone was mentioned when going from non-polar organic solvents to water. The hydrophobic effect could be at least to some extent involved, since additives, such as glucose or saccharose, accelerate the reaction even more [72]. Cetyltrimethylam-monium chloride as an amphiphilic species which can influence the hydrophobic interactions was found to promote the Michael reaction of various nitroalkanes with conjugated enones in dilute aqueous solutions of sodium hydroxide [73],... 

Additions and condensations. Nitroalkanes form adducts with enones in aqueous media in the presence of cetyltrimethylammonium chloride. ... 

Scheme 3.20 Enantioselective Michael addition of nitroalkanes to cyclic enones catalyzed by chiral secondary amines.

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