Conjugate addition of 1,3-dicarbonyl compounds

Recently, very effective asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported, as shown in Scheme 4.10. The reaction of ethyl acetoacetate with nitrostyrene is carried out in the presence of 5 mol% of the preformed complex of magnesium triflate and chiral bis(oxazoline) ligands and a small amount ofW-methylmorpholine (NMM) to give the adduct with selectivity of 91%. The selectivity depends on ligands. The effect of ligands is presented in Scheme 4.10.63... 

In 2003, Takanoto et al. reported the first highly enantioselective organocatalytic conjugate addition of 1,3-dicarbonyl compounds to nitroolefins catalyzed by bifunctional thiourea-amine catalyst 142 (Fig. 2.15)[238]. After Takemoto s report a wide... 

Fig. 2.19 Proposed transition states for the conjugate addition of 1,3-dicarbonyl compounds to nitroolefins...

In addition to the electron-deficient olefins, alkynones were also suitable electrophiles. In 2004, Jprgensen and Bella [88] developed the first organocatalytic enantioselective conjugated addition of 1,3-dicarbonyl compounds to alkynones utilizing cinchona alkaloids catalyst 85 (Scheme 5.43). Both aromatic and aliphatic... 

Among the most successful catal)rtic systems employed in enantioselective nickel-catalysed Michael additions of nucleophiles to nitroalkenes is that developed by Evans and Seidel in 2005, which allowed enantioselectivities of up to 95% ee to be achieved in the enantioselective conjugate additions of 1,3-dicarbonyl compounds to nitroalkenes (Scheme 2.3). Products resulting... 

Scheme 2.5 Conjugate additions of 1,3-dicarbonyl compounds to nitroalkenes with a preformed diamine nickel catalyst.

Catalytic enantioselective conjugate addition of 1,3-dicarbonyl compounds (199) to nitroalkenes (200) has been attained in the presence of (TfO)2Mg (5 mol%) and (201) as chiral ligand with up to 95%... 

The development of a highly enantioselective catalytic asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes is described, as is its use in the synthesis of the selective endothelin A antagonist ABT-546. Employing 4 mol% of a bis(oxazoline)-Mg(OTf)2 complex with 5.5 mol% of an amine co-catalyst, the product nitroketone is obtained in 88% ee, with good yields. Particularly important to the reaction is the water content. While water is necessary during the generation of the catalyst, the water must then be removed in order to maximize selectivity and reactivity. The scope of the reaction has been extended to other ketoester and malonate nucleophiles, as well as other nitroolefins. 

In recent years, various studies were reported on the asymmetric conjugate addition of nucleophiles to unsaturated compounds as catalyzed by natural cinchona alkaloids (3). For example, conjugate 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... 

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. 

The first report on the development and use of chiral squaramide derivatives as hydrogen-bond donor catalysts appeared in 2008 by Rawal and coworkers [78]. The authors showcased the usefulness of this new scaffold by evaluating the Michael addition of 1,3-dicarbonyl compounds to nitroalkenes, the same reaction that was used to illustrate the capabihty of a thiourea catalyst by Takemoto [45]. Of the catalysts examined, the cinchonine-derived squaramide 13 functioned well as a bifunctional catalyst and provided the conjugate addition product in high yield and excellent enantioselectivity (Scheme 10.12). Less reactive substrates such as a-substituted 1,3-dicarbonyl compounds also participate in the desired reaction. 

Terada, M., Ube, H. and Yaguchi, Y. (2006) Axially chiral guanidine as enantioselective base catalyst for 1,4-addition reaction of 1,3-dicarbonyl compounds with conjugated nitroalkenes. Journal of the American Chemical Society, 128, 1454-1455. 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

The majority of recent contributions for the conjugate addition of C-H acids to a,p-unsaturated carbonyl compounds catalysed through iminium ion intermediates have come from the laboratories of Jprgensen. The ease with which 1,3-dicarbonyl compounds and nitroalkanes can be deprotonated, together with the soft nature of the nucleophile mean this is a particularly facile reaction which conveniently leads to useful precursors for further synthetic manipulation. 

Scheme 22 Conjugate addition of cyclic 1,3-dicarbonyl compounds to a,p-unsaturated ketones...

The disulfide dimers of 2-aminothiophenols have also been used in the syntheses of benzothiazines. In this case, nitrogen acts as a nucleophile and sulfur as an electrophile. Reagents that have nucleophilic carbons adjacent to an electrophilic carbon can be reacted with these disulfides. Examples include a,(3-unsaturated esters that undergo conjugate addition followed by enolate addition to sulfur (Equation 86) <1983J(P1)567>, and 1,3-dicarbonyl compounds such as ethyl acetoacetate <2005AXEo2716> and dimethyl malonate <2006ARK(xv)68> (Scheme 63). 

Jacobsen et al. have shown that cyanoacetate derivatives undergo conjugate addition to ,/i-unsaturated imides in the presence of a chiral Al-oxo salen complex 32 to afford the corresponding product in up to 98% ee (Scheme 16) [19]. When an a-amino cyanoacetate was used, a highly functionalized lactam 33 was obtained in one step. Another example of Lewis acid-catalyzed conjugate addition of cyclic 1,3-dicarbonyl compounds to 2-oxobutenoate employed the chiral Cu-bisoxazoline complex 34 (Scheme 17) [20]. 

The double conjugate addition of dithiols to propargylic ketones offers a facile route to [3-keto 1,3-dithianes that can function as masked 1,3-dicarbonyl compounds and provide access to spiroketals. When the alkynic substrate contains an additional electrophilic centre, a tandem eyclisation can accompany thiane formation (Scheme 30) <03OBC15>. 

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