Michael addition of 1,5-dicarbonyl compounds

The asymmetric Michael addition of 1,3-dicarbonyl compounds to nitrostyrene is promoted by chiral alkaloid catalysts to give the addition products in good chemical yield, but the enantioselectivity is rather low (Eq. 4.47).62... 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Dicarbonyl compounds are widely used in organic synthesis as activated nucleophiles. Because of the relatively high acidity of the methylenic C—H of 1,3-dicarbonyl compounds, most reactions involving 1,3-dicarbonyl compounds are considered to be nucleophilic additions or substitutions of enolates. However, some experimental evidence showed that 1,3-dicarbonyl compounds could react via C—H activations. Although this concept is still controversial, it opens a novel idea to consider the reactions of activated C H bonds. The chiral bifunctional Ru catalysts were used in enantioselective C C bonds formation by Michael addition of 1,3-dicarbonyl compounds with high yields and enantiomeric excesses. ... 

Scheme 5.20. Asymmetric Michael addition of 1,3-dicarbonyl compounds.

Michael addition of 1,3-dicarbonyl compounds to conjugated prochiral nitroalkenes catalysed by (acac)2Ni and (acac)2Co has been reported to give up to 30% ee when carried out in the presence of cinchonidine.100... 

The axially chiral guanidine catalyst (155) (0.4-5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds (g to a broad range of conjugated nitroalkenes (<98% ee).211... 

A highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported that employs a newly developed Ni(II)-(bis)diamine-based catalyst (174). The reaction scope includes substituted and unsubstituted malonates, /3-keto esters, and nitroalkenes bearing aromatic and aliphatic residues.202... 

Indium-catalyzed Michael addition of 1,3-dicarbonyl compounds to but-2-ene-1,4-diones, followed by cyclization and dehydration gave rise to the formation of tetrasubstituted furans in high yields. An example is shown below <07TL2573>. 

Carbon-carbon bond formation via the Michael addition of a,P-unsaturated ketone and 1,3-diketone is achieved in high yields and short times to give (61) by employing catalytic amounts of EUCI3 in dry media under microwave irradiation (Soriente et al, 1997). Ranu et al. (1997) reported the Michael addition of ethyl acetoacetate, acetyl acetone, and ethyl cyanoacetate to cycloalkenones, P-substituted enones and enal. The reaction accomplished efficiently on the surface of alumina under microwave irradiation in dry media. Baruah et al. (1997a,b) also demonstrated the BiClj and Cdl2 catalyzed solvent-free Michael addition of 1,3-dicarbonyl compounds under microwave irradiations with good yields. 

Baruah, B., Boruah, A., Prajapati, D., and Sandhu, J.S., 1997a. BiClj or Cdlj catalyzed Michael addition of 1,3-dicarbonyl compounds under microwave irradiations. Tetrahedron Letters, 38 1449-50. 

Soriente, A., Spinella, A., De Rosa, M., Giordano, M., and Scettri, A. 1997. Solvent-free reaction under microwave irradiation A new procedure for Eu+ —Catalyzed Michael addition of 1,3-dicarbonyl compounds. Tetrahedmn Letters, 38 289-90. 

In recent years, many chiral catalysts for the enantioselective synthesis of optical active 1,5-dicarbonyl compounds have been developed, such as chiral crown ethers with potassium salt bases and chiral palladium complexes, including bimetallic systems. Nakajima and coworkers reported on enantioselective Michael reactions of S-keto esters to a,/3-unsaturated carbonyl compounds in the presence of a chiral biquinoline N,N dioxide-scandium complex, which catalyzed the additions in high yields and with enan-tioselectivities up to 84% ee . Kobayashi and coworkers found that the combination of Sc(OTf)3 with the chiral bipyridine ligand 149 (equation 41) was also effective as a chiral catalyst for asymmetric Michael additions of 1,3-dicarbonyl compounds 147 to a,/3-unsaturated ketones 148. The corresponding Michael adducts 150 were obtained in good to high yields with excellent enantiomeric excesses in most cases (Table 10). 

BiX mediates the Mukaiyama-Michael addition of a./i-urisaluraled carbonyl compounds (Scheme 14.87) [171, 172 b, c]. The BiCb-catalyzed Michael addition of 1,3-dicarbonyl compounds to methyl vinyl ketone and benzal acetophenone proceeds efficiently under microwave irradiation [179]. The Knovenagel condensation of aldehydes with active methylene compounds can also be promoted by BiCl3 (Scheme 14.88) [180]. 

Rann et al. reported the dramatic influence of a new tailor-made, task-specific, and stable ionic liquid, butyl methyl imidazolium hydroxide ([bmim][OH]), in Michael addition. They have discovered that a task-specific ionic liqnid [bmim][OH] efficiently promoted the Michael addition of 1,3-dicarbonyl compounds, cyano esters, and nitro alkanes to a variety of conjugated ketones, carboxylic esters, and nitriles withont reqniring any other catalyst and solvent (Fig. 12.21) [16]. Very interestingly, all open-chain 1,3-dicarbonyl componnds such as acetylacetone, ethyl ace-toacetate, diethyl malonate, and ethyl cyanoacetate reacted with methyl vinyl ketone and chalcone to give the usual monoaddition products, whereas the same reactions with methyl acrylate or acrylonitrile provided exclusively bis-addition products. 

Bensa, D., Constantieux, T. and Rodriguez, J. (2004) P-BEMP a new efficient and commercially available user-friendly and recyclable heterogeneous organocatalyst for the Michael addition of 1,3-dicarbonyl compounds. Synthesis, 923-927. 

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. 

Michael addition of 1,3-dicarbonyl compounds to nitroalkenes with subsequent cyclization and loss of HNO2 yields furans (Equation (33)). 4,5-Annulated furans are also available by this route <57CB1215, 59LA(626)71, 78JCS(P1)1144, 80JOC2945, 83IJC(B)914, 8381027). 

Very high enantioselectivities in the PTC Michael addition of 1,3-dicarbonyl compounds to enones have been achieved by Maruoka et al. [189,233] As shown in Scheme 2.86, just a 2 mol% of the binaphthyl-derived phase-transfer catalyst 124b [Scheme 2.70, 124, Ar=3,5-((CFj)jC H3)] in the presence of 10 mol% of solid KjC03, is able to achieved a highly efQdent and enantioselective addition of 2-(9-fluorenoxycarbonyl)cyclopentanone to methyl vinyl ketone [189]. 

S.2.4.3. oL,p-Unsaturated Ketones as Acceptors. The earliest studies on the organocatalytic asymmetric Michael reactions were reported by the group headed by Wynberg [1,83]. The authors found that natural cinchona alkaloids could effectively promote the Michael addition of 1,3-dicarbonyl compounds to a,(3-unsaturated enones. In 2003, Jprgensen and co-workers [84] developed the first highly... 

In summary, a catalytic asynometric Michael addition of 1,3-dicarbonyl compounds to nitroalkenes was developed. This reaction was employed in the synthesis of ABT-546 in order to prepare multi-kilogram lots for toxicology and clinical studies. The reaction scope has been found to include a variety of ketoesters, as well as malonates and nitroalkenes. 

Subsequently, several groups have studied related squaramide-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes. High enantioselectivities have been achieved using pyrrolidine-cinchonine-squaramide catalyst 14 [81], quinine-squaramide catalyst 15 [82, 83], and Cs-symmetrical cinchonine-squaramide catalyst 16 (Figure 10.4) [84]. Notably, the reaction time... 

Boddaert T, Coquerel Y, Rodriguez J. Organocatalytic activity of A-heterocyclic carbenes in the Michael addition of 1,3-dicarbonyl compounds application to a stereoselective spiro-cyclization sequence. Afilv. Synth. Catal. 2009 351 1744-1748 (erratum Ibid 2541). 

CATALYTIC ENANTIOSELECTIVE MICHAEL ADDITION OF 1,3-DICARBONYL COMPOUNDS TO CYCLIC ENONE FOR THE SYNTHESIS OF THE STRYCHNOS ALKALOIDS AND MAGNOLIONE ANALOGS... 

Other Metal Complexes Apart from metal complexes derived from BINOL, other metal complexes, such as the lithium-aluminum amiuo diol complex, " aluminum and nickel salen complex, ruthenium diamine complex, and ruthenium phosphinite diamine complex were also found applicable for the asymmetric Michael addition of 1,3-dicarbonyl compound to cyclic enone. All these metal complexes afforded about 90% of asymmetric induction in the Michael reaction of 2-cyclohexen-l-one and malonate. 

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