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Friday, February 4, 2005
M. Manuel B. Marques
REQUIMTE - FCT - New University of Lisbon

Copper-Catalyzed Conjugate Addition to α,β-Unsaturated Carbonyl Compounds

Conjugate addition (CA), and in particular the conjugate addition of organometallic reagents to α,β-unsaturated carbonyl compounds, is a useful method in organic synthesis. Recent improvements have been reported that provide enantioselective procedures using new chiral ligands. Strategies to control stereochemistry at the β-position using catalytic systems have been reviewed by Norbert Krause and Anja Hoffmann-Röder (Synthesis 2001, 171. ). This highlight focuses on the most recent achievements in copper-catalyzed CA.

The Feringa group reported (PNAS 2004, 101, 5834. ) a copper-catalyzed asymmetric CA of Grignard reagents to cyclic enones with high stereocontrol and up to 96% ee. The copper catalyst was either CuCl or CuBr•SMe2 and commercially available ferrocenyl diphosphines served as the chiral ligands (Scheme 1, Figure 1).

Scheme 1 – CA of Grignard reagents to cyclic enones catalyzed by copper.

Among the wide variety of ferrocenyl-based diphosphine ligands tested, promising results were achieved when TaniaPhos (4) and JosiPhos (9) (Figure 1) were used. These ligands provided regioselectivity of up to 95% and 56-96% ee.

Figure 1 – Chiral ferrocenyl diphosphines

According to the authors, an important factor for the success of these chiral catalysts is to avoid the presence of free copper salts and Grignard reagents simultaneously. Regioselectivity was affected when different halides (in the copper salt or Grignard reagent) were used, however enantioselectivity was not. The same group also investigated the effect of branched-chain alkyls in the Grignard reagent resulting in low ees, the influence of ligand structural features, and application of the copper-catalyzed CA to other cyclic enones (cycloheptenone, cyclopentenone).

The Feringa group has recently (J. Am. Chem. Soc. 2004, 126, 12784. ) applied this methodology to acyclic aliphatic enones with high regio- and enantioselectivity (Scheme 2, Figure 2).

Scheme 2 – Enantioselective CA of Grignard reagents to acyclic enones catalyzed by copper.

This group has also found that with TaniaPhos (4) ligand (Figure 1), the addition of EtMgBr to enone 11 (with R1 = n-pent; R2 = Me, R3 = Et) in the presence of CuCl resulted in a poor enantioselectivity, although good regioselectivity was achieved. However, good selectivity was obtained with JosiPhos (9) (90% ee, 94% yield).

Figure 2 – Chiral ferrocenyl-based diphosphines used by the Feringa group in CA to acyclic enones.

Several sets of experimental conditions were tested. Steric hindrance in the Grignard and enone structure were investigated. Asymmetric copper-catalyzed CA is not limited to enones where the β-substituent is aliphatic, since successful results were also obtained with aromatic substituents. The authors applied this method to (Z)-enones with 90-96% ee, showing once more the versatility of the method.

Bergdahl and co-workers reported (Org. Lett. 2004, 6, 107. ) a new, one-pot procedure for CA of alkenyl groups from alkenyl zirconocene to α,β-unsaturated ketones and aldehydes catalyzed by CuI•0.75 DMS (Scheme 3).

Scheme 3 – CA of alkenyl zirconocene reagents to α,β-unsaturated ketones and aldehydes catalyzed by CuI•0.75 DMS.

The reported procedure consisted of addition of 10 mol% of the CuI•0.75 DMS catalyst to 1.0 equiv of an alkenyl zirconocene. The resulting addition product with α,β-unsaturated aldehydes or ketones was isolated in high yields (54-97%). A wide variety of enones and enals were tested, including cyclic ketones (five- and six-membered rings) and acyclic ketones, as well as various alkynes. This catalyst was shown to be efficient and flexible.

Recently, the Bergdahl group published (J. Org. Chem. 2005, 70, 580. ) a CA of a monosilylcuprate reagent to α,β-unsaturated carbonyl compounds in the presence of dimethylsulfide (DMS), thus avoiding the use of additives. Scheme 4 shows a representative example of this procedure.

Scheme 4 – CA of monosilylcopper reagent in the presence of copper-solvating species (DMS or THF) – preparation of β-silylated 1,4-addition products.

The DMS influence in the CA of the Li[PhMe2SiCuI] complex is very important, and it is recommended by the authors that CuI should be purified via its DMS complex (CuI•0.75 DMS); indeed this organosilylcuprate reagent is more reactive when DMS is used as solvent in the CA. Their procedure gives high yields and stereocontrol in the preparation of useful products with the formation of a C-Si bond, and even works with sterically hindered β,β-disubstituted enones.

M. M. B. Marques, Org. Chem. Highlights 2005, February 4.