Malonate, asymmetric Michael addition

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. 

Figure 6.18 Chiral amine 56 and thiourea derivatives (10mol% loading) screened in the asymmetric Michael addition of diethyl malonate to trcms-P-nitrostyrene in toluene.

Scheme 6.56 Typical products of the asymmetric Michael addition of dialkyl malonates to frans-P-nitrostyrenes in the presence of 12.

Scheme 6.61 Mechanistic proposals of the 12-catalyzed asymmetric Michael addition of diethyl malonate to trans-P-nitrostyrene proposed by the Takemoto group (A, B, and C) and initial enolate complex (D) with the ammonium group as additional hydrogen-bond donor initiating an alternative mechanism suggested by Sods, Ptipai, and coworkers.

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.

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... 

Cobalt(II) complexes prepared in situ from (AcO Co and two novel chiral spiro nitrogen-containing ligands, 7,7/-bis(2-pyridinecarboxamido)-l,l/-spirobiindane (SIPAD) and 7,7/-bis(2-quinolinecarboxamido)-l,l/-spirobiindane (SIQAD), are efficient cata- lysts for the asymmetric Michael addition of malonates to chalcone derivatives. The alkylation products were obtained in high yields with moderate enantioselectives.169... 

Modified cinchona alkaloids 18 and 19, derived from quinine and quinidine, respectively, were utilized by Deng and co-workers for the catalytic asymmetric Michael additions of malonates to nitroolefins [49]. These catalysts effectively promoted the conjugate additions of methylmalonate to a variety of aromatic (90-99% yield 96-98% ee), heteroaromatic (97-99% yield 96-98% ee) and aliphatic (71-86% yield 94% ee) -substituted nitroolefins (Table 6.7). As the two alkaloids... 

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. 

The first chiral aluminum catalyst for effecting asymmetric Michael addition reactions was reported by Shibasaki and coworkers in 1986 [82], The catalyst was prepared by addition of two equivalents of (i )-BINOL to lithium aluminum hydride which gave the heterobimetallic complex 394. The structure of 394 was supported by X-ray structure analysis of its complex with cyclohexenone in which it was found that the carbonyl oxygen of the enone is coordinated to the lithium. This catalyst was found to result in excellent induction in the Michael addition of malonic esters to cyclic enones, as indicated in Sch. 51. It had previously been reported that a heterobimetallic catalyst prepared from (i )-BINOL and sodium and lanthanum was also effective in similar Michael additions [83-85]. Although the LaNaBINOL catalyst was faster, the LiAlBINOL catalyst 394 (ALB) led to higher asymmetric induction. 

The catalyst prepared from aminodiol 420 was also examined for its capacity to effect asymmetric Michael addition of a malonate to an acyclic enone. The single example reported is shown in Sch. 58 and occurs with significantly lower asymmetric... 

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... 

In 2004, Deng and coworkers reported the first preparatively useful results for the catalytic asymmetric Michael additions of malonates to nitrooleftns. They found that... 

Table 9. Effect of a chiral catalyst on the asymmetric Michael addition of diethyl acetamido malonate on chalcone...

In 1974,Mukaiyama and co-workers reported the first examples of Lewis acid-catalyzed Michael reactions between silyl enolates and a,p-unsaturated carbonyl compounds [33]. Evans and co-workers developed a catalytic asymmetric Michael reaction of silyl enol ethers of thiol esters to alkylidene malonates. For example, the reaction of alkylidene malonate 23 with 2.2 equiv of silyl enol ether 22 was carried out in the presence of 10 mol % of catalyst 25 and 2 equiv of hexa-fluoro-2-propanol (HFIP) in PhMe/CH2Cl2 (3 1) at -78 °C to give the expected adduct 24 in 93% ee (Scheme 5) [34]. Borane complex-catalyzed asymmetric Michael addition has also been reported [35]. 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Scheme 5.4. Asymmetric Michael addition between malonates and enones catalyzed by NAP-MgO in the presence of a chiral auxiliary.

NAP-MgO acts as a bifunctional heterogeneous catalyst for the Claisen-Schmidt condensation (CSC) of benzaldehydes with acetophenones to yield chalcones, followed by asymmetric epoxidation (AE) to afford chiral epoxy ketones in moderate to good yields and impressive enantioselectivities (ee s). NAP-MgO, in combination with the chiral auxiliary (11 ,21 )-(- -)-1,2-diphenyl-1,2-ethylenediamine (DPED), catalyzed the asymmetric Michael addition of malonates to cyclic and acyclic enones. 

Scheme 14.1 Asymmetric Michael addition of dimethyl malonate to nitroalkenes.

Scheme 14.3 Asymmetric Michael addition of malonates to nitroalkenes catatysed by NaCPN in water.

The catalytic performance of the lithium salt of (5)- or (f )-3,3 -bis[bis-(phenyl) hydroxymethyl]-2,2 -dihydroxy-dinaphthalene-l,l (4, BIMBOL) in asymmetric Michael additions of malonic acid derivatives and toluedine has been studied. Using nitrostyrene and cyclohex-2-enone as Michael acceptors efficient asymmetric C-C and C-N bond formations with up to 95% ee at room temperature were observed. A transition-state model of the malonic ester addition to cyclohex-2-enone has been proposed based on the molecular stmcture of the acetone solvate of BIMBOL. 

As a direct route for the constructing carbon-carbon bonds, catalytic asymmetric Michael additions with various carbon-based nucleophiles including malonic esters, cyanide, electron-deficient nitrile derivatives, a-nitroesters, nitroalkanes, Horner-Wadsworth-Emmons reagent, indoles, and silyl enol ethers have attracted considerable attention. 

Furthermore, three-component coupling tandem Michael-aldol reactions were achieved by trapping the aluminium enolate intermediate with an aldehyde (Scheme 19.16a). Initiated by the asymmetric Michael addition of malonic esters to cyclic enones, several natural products were synthesised... 

A series of lithium salts of protected primary amino acids (105, n = 0-2) catalyse asymmetric Michael addition of malonates to 2-cyclohexen-l-one. The -amino salt (n = 1) gave higher ee than either the y- or the a-. A mechanistic study using DPT has been carried out to identify how the -amino salt better coordinates the imine intermediate and maximizes ee. 

Michael addition of arylnitroalkenes to indole affords 3-(P-nitroalkyl)indoles 23 [143] in the presence of the Zn(OTf)2-complex with a chiral bisoxazoline ligand high stereoselectivities are observed [144], Likewise, benzylidene malonates undergo highly selective asymmetric Michael addition to the 3-position of indole ( 25) in the presence of a Cu(OTf)2-complex with a chiral bisoxazoline [145], To the group of Michael addition-related indole reactions (formally) belong the FeCls-catalyzed addition of acety-lacetone [146] and the Sc(OTf) 3-catalyzed addition of the acylaUene 26 [147] to afford 3-substituted indole derivatives 27. 

Scheme 14.3 shows the effect of the organocatalyst in the asymmetric Michael addition of malonic derivative 16 on cinnamaldehyde 15. After cyclization, water is expelled to form the A/-acyliminium intermediate 20 that is prone to Mannich-type addition of the indole. This addition generates the spirocyclic secoyohimbane scaffold and the unstable imidoyl bromide 21 that is hydrolyzed by the previously liberated water. This terminates the cascade and provides the spiroindolone with four stereo-centers. 

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