Michael additions of dimethyl malonate

Figure 6.40 (Thio)urea catalysts derived from dihydroquinine and dihydroquinidine screening results obtained from the asymmetric Michael addition of dimethyl malonate to frans-p-nitrostyrene.

The intramolecular asymmetric Michael reaction of acyclic compounds obtained from chiral alkaloid building blocks using amines and (5)-proline has been investigated. " The Michael addition of dimethyl malonate to a,p-unsaturated aldehydes proceeds... 

Very recently, Ikariya reported chiral amido ruthenium complex-catalyzed asymmetric Michael addition of dimethyl malonate with conjugate enones using Ru[(i ,i )-TsDPEN](>7 -arene) ((R,R)-TsDPEN = (lR,2R)-N-(p-toluenesulfonyl)-l,2-di-phenylethylenediamine) [84], The reaction of cyclopentenone with dimethyl malonate gave the corresponding /3-alkylation product in 99% yield with 97% e.e. (Eq. 9.60). For this mthenium-catalyzed asymmetric Michael addition, the Bronsted basicity of the amido ligand is responsible for the excellent catalytic activity. 

In another approach, the a-pyrone ring was made by Michael addition of dimethyl malonate to 3j -hydroxy-21-oxo-20-methylenepregn-5-ene (506),... 

Plaquevent and coworkers synthesized methyl dihydrojasmonate 28 using this methodology by performing the asymmetric Michael addition of dimethyl malonate 29 on 2-pentyl-2-cydopentenone 30 [18]. The mechanism involved the tandem deprotonation of the malonate 29 using solid-liquid phase-transfer catalysis... 

Allylic and dienyl sulfones have been prepared by conjugate addition to 1,3-dienes ". Phenylsulfonyhnercuration of conjugated dienes gives mercury adducts which can be treated with base to afford phenylsulfonyldienes. 2-(Phenylsulfonyl)-l,3-dienes can be stereo- and regioselectively functionalized via Michael addition of nucleophiles to give allylic sulfones. A key intermediate in the synthesis of a Monarch butterfly pheromone 4 was prepared by BackvaU and Juntunen by alkylation and subsequent palladium-catalyzed substitution of the allylic sulfone formed by Michael addition of dimethyl malonate to 2-(phenylsulfonyl)-l,3-butadiene (equation 10). 

Evidently, although the system tolerates both aromatic and aliphatic aldehydes, the introduction of an electron-withdrawing substituent on the aromatic substrate results in a decreased yield. To gain information about the mechanism of the overall tandem reaction, kinetic studies were carried out to identify the rate-determining step. Changing the catalyst concentration in the reaction between 3-methylbutyraldehyde, nitromethane and dimethyl malonate revealed that the reaction is first order in nickel catalyst, indicating that the Michael addition of dimethyl malonate to the nitroalkene is the ratedetermining step. 

Michael additions of dimethyl malonate and dibenzoylmethane to conforma-tionally flexible 3-C-nitro-2-enopyranosides 46 and 47 have been found to take place exclusively trans to the aglycon generating 48 and 49 respectively. Thus addition of the nucleophile to the a-glycoside 46 took place with the Michael acceptor in the conformation and the p-glycoside 47 reacted in the Ho conformation. Addition of 2,4-pentanedione and ethyl acetoacetate, on the other hand, was accompanied by further intramolecular cyclization reaction to yield bicyclic products 50 and 51 from 46 and 47 respectively. ... 

Scheme 14.1 Asymmetric Michael addition of dimethyl malonate to nitroalkenes.

Beyond secondary amines, various chiral Brpnsted acid and hydrogen-bonding donor catalysts, supported primary amines were also demonstrated to be suitable catalysts to implement metal/organic binary catalytic systems. In 2006, McQuade et al. reported a cascade three-component reaction by combining encapsulated amine and nickel catalysts with high reactivity and chemoselectivity [81]. The reaction proceeded through an encapsulated amine-promoted nitroalkene formation via iminium ion intermediate followed by a nickel complex-promoted chemoselective Michael addition of dimethyl malonate to the newly generated nitroalkene (Scheme 9.76). 

Among metal-BINOL complex catalysts developed by Shibasaki et al., (I )-ALB is found to be the most effective catalyst for the asymmetric Michael addition of malonate to 2-cyclohexen-l-one. In 1998, Shibasaki et al. further fine-tuned the reaction 9onditions by adding the base (e.g., KO-r-Bu) and MS (4 A) to the system. These optimizations accelerate the catalytic asymmetric Michael addition without lowering the enantioselectivity. They suggested that the base was used to activate the Aluminum-Lithium-BINOL (ALB) complex. The 4-A molecular sieve (MS) was used to remove the trace amount of H2O that could otherwise gradually lead to ALB-KO-f-Bu catalyst decomposition. In the presence of ALB (0.3 mol%), KO-f-Bu (0.27 mol%), and 4-A MS, the Michael addition of dimethyl malonate to cyclohex-2-enone proceeded smoothly to give 94% product yield with 99% ee even at room temperature. Particularly noteworthy was that this reaction could be carried out on a 100-g scale without deleterious effect. Later, Xu and co-workers modified and streamlined the work-up procedures... 

I.3.I. Chiral Phase-Transfer Catalysis The exploration of modified cinchona alkaloid organocatalysts for asymmetric synthesis indicates that the quaternary ammonium salt derived from cinchona alkaloids is one of the best catalysts in the asymmetric Michael reaction. In 2000, Perrard and co-workers used A/-meth-ylanthracenylquininium (or quinidinium) chloride salt (Q-a or QD-a) for catalyzing the asymmetric Michael addition of dimethyl malonate to 2-pentyl-2-cyclo-penten-l-one (Scheme 9.6). ... 

SCHEME 9.6. Af-Methylanthracenylquininium (or quinidinium) chloride salt for catalyzing the asymmetric Michael addition of dimethyl malonate to 2-pentyl-2-cyclopenten-l-one. 

Scheme 5.5 The dual catalyst system gives access to intermediate 4, which gives the otherwise inaccessible Michael adduct 6 after addition of dimethyl malonate (DMM) instead of the dinitro product 5 [19].

Papai et al. selected as model reaction the addition of 2,4-pentanedione (acetylacetone) to trans-(R)-mtrostyvQnQ, catalyzed by the bifunctional thiourea catalyst shown in Scheme 6 [46]. The analogous Michael-addition involving dimethyl malonate and nitroethylene as substrates, and a simplified catalyst was calculated at the same level of theory by Liu et al. [47]. Himo et al. performed a density functional study on the related cinchona-thiouTQa catalyzed Henry-reaction between nitromethane and benzaldehyde [48]. 

A chiral phase transfer catalyst was dissolved in ionic liquid media for the enantioselective Michael reaction of dimethyl malonate with l,3-diphenylprop-2-en-l-one with K2CO3 203). The phase-transfer catalyst was a chiral quininium bromide (Scheme 20). The reaction proceeded rapidly with good yield and good enantioselectivity at room temperature in all three ionic liquids investigated, [BMIM]PF6, [BMIM]BF4 and [BPy]BF4. In the asymmetric Michael addition, the enantioselectivity or the reaction in [BPy]Bp4 was the same as in conventional organic solvents. 

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... 

The Michael addition of oxygen nucleophiles to vinyl sulfones185 and the addition of dimethyl malonate and ethyl cyanoacetate to a,fl-unsaturated sulfones in the presence of Triton-B and K2CO3 have been studied.186... 

In 1979, Tsuji s group [51] reported an alternative approach to macrolactonization. Inspired by their previous success in the preparation of recifeiolide and 9-decanolide, the authors envisioned that the dimethyl ether of zearalenone (6) could be obtained via olefination using the co-iodoalkyl phenylthioacetate 7 (Scheme 7.2). The Michael addition of diethyl malonate (11) to 10 followed by decarboxylation afforded an ethyl ester, which was reduced to alcohol and converted into the tosylate 12. Wacker-Tsuji oxidation of the terminal olefin was then followed by reduction of the ketone and conversion of the tosylate into iodide to provide 9. This was... 

The application of 3-aminopropyl phosphine (3) [41,46] as a building block for incorporation into -COOH functionalized frameworks provides an excellent example of the utility of preformed primary phosphine frameworks (Scheme 8) [46]. The reactions involved Michael addition of ferf-butyl acrylate to malonic acid dimethyl ester to produce the intermediate adduct, 2-methoxycarbonyl-pentanedioc acid 5-ferf-butyl ester 1-methyl ester, which upon treatment with trifluro-acetic acid (TFA) produced the corresponding diester acid,2-methoxy-carbonyl-pentanedioic acid 1-methyl ester, in near quantitative yield. It is remarkable to note that the reaction of NH2(CH2)3PH2 (3) with the diester acid is highly selective as the -COOH group remained unattacked whereas the reaction occurred smoothly and selectively at the -COOMe groups to pro-... 

Reactions of a,(3-unsaturated acylzirconocene chlorides with stable carbon nucleophiles (sodium salts of dimethyl malonate and malononitrile) at 0°C in THF afford the Michael addition products in good yields (Scheme 5.38). Direct treatment of the reaction mixture with allyl bromide in the presence of a catalytic amount of Cul -2LiCl (10 mol%) in THF at 0 °C gives the allylic ketone in a one-pot reaction. This sequential transformation implies the electronic nature of a,P-unsaturated acylzirconocene chloride to be of type E as shown in Scheme 5.37. 

A series of diaryl-2-pyrrolidinemethanols have been tested as catalysts for the enan-tioselective Michael addition of malonate esters to nitroalkenes.30 Bis-(3,5-dimethyl-phenyl)[(S)-pyrrolidin-2-yl]methanol (6), easily prepared from L-proline, has been found the most efficient bifunctional organocatalyst, providing up to 56% ee. 

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