Enantioselective Friedel–Crafts Alkylation of Indoles with β,γ-Unsaturated α-Ketoesters Catalyzed by New Copper(I) Catalysts

Abstract

New Cu(I) catalysts are effective in enantioselective Friedel–Crafts alkylation of a variety of indoles with different β,γ-unsaturated α-ketoesters. A control study shows that such a catalyst system is less sensitive to air, and the reactions can be carried out without special cares such as glovebox operation or moisture/oxygen-free conditions. Preliminary computation results suggest that there exists π–π stacking between the substrate and the catalyst, and such an interaction seems to play a role in stabilizing the reaction intermediate and enhancing the stereoselectivity of the reactions. The desired products can be obtained in up to 98% yield at 99% enantiomeric excess. The same high enantioselectivity can be observed when the reaction is carried in a gram scale, indicating a good scalability of the catalyst system in enantioselective Friedel–Crafts alkylation of different indoles with β,γ-unsaturated α-ketoesters.

Cu(II)‐Catalyzed Enantioselective Aza‐Friedel‐Crafts Reaction of 1‐Naphthols and Electron‐Rich Phenols with Isatin‐Derived Ketimines

“…In the case of C11 , nitrogen atom of the proline moieties adopted ( S )‐configuration (denoted as C11 ‐N( S ), Scheme 4). [18] This is also in agreement with our previous X‐ray diffraction result on the similar imidazoline‐containing chiral ligand [17] …”

“…Previously, we found that connecting different proline moieties to binaphthyl skeletons provided chiral ligands which could take the advantages of both the proline moiety and the binaphthol structure. Catalysts bearing binaphthyl-prolinebased tridentate ligands L1-L8 were effective in enantioselective Henry reactions, [12] enantioselective addition of alcohols and t-butyl hydroperoxide to isatin-derived N-Boc ketimines, [13] enantioselective addition of malonates to β,γ-unsaturated αketoesters, [14] and enantioselective Friedel-Crafts alkylation of indoles with β,γ-unsaturated α-ketoesters [15] or isatin-derived N-Boc ketimines. [16] Studies showed that the axial chirality of the binaphthyl skeleton and the central chirality of the proline moiety in these ligands should match with each other, and the substituents R in chiral ligands L1-L8 exhibited drastic effect on the stereofacial selection in asymmetric Henry reaction.…”

“…Previously, we found that connecting different proline moieties to binaphthyl skeletons provided chiral ligands which could take the advantages of both the proline moiety and the binaphthol structure. Catalysts bearing binaphthyl‐proline‐based tridentate ligands L1 – L8 were effective in enantioselective Henry reactions, [12] enantioselective addition of alcohols and t‐butyl hydroperoxide to isatin‐derived N‐Boc ketimines, [13] enantioselective addition of malonates to β,γ‐unsaturated α‐ketoesters, [14] and enantioselective Friedel–Crafts alkylation of indoles with β,γ‐unsaturated α‐ketoesters [15] or isatin‐derived N‐Boc ketimines [16] …”

“…In this type of chiral ligands, the steric feature could be altered by the use of substituents R 3 /R 4 with different sizes, and the electronic property could be fine‐tuned by introducing different substituents R 2 to sp 3 nitrogen atom of the imidazoline moiety. Studies showed that in the presence of appropriate amount of in situ prepared chiral catalyst, enantioselective addition of 4‐hydroxycourmarins to β,γ‐unsaturated α‐ketoesters proceeded readily, giving the desired products in up to 99 % yield and up to 99 % ee [17] …”

Enantioselective Michael addition of malonates to β,γ-unsaturated α-ketoesters catalysed by Cu(ii) complexes bearing binaphthyl–proline hybrid ligands

“…12 This ligand was further found to be effective in the Friedel-Crafts reaction of β,γ-unsaturated α-ketoesters with indoles. 13 In the presence of L7, CuOTf-catalysed reactions gave the desired products in high yields and up to 99% ee. A preliminary study suggested that β,γ-unsaturated α-ketoester bound to the central metal in a mono-dentate way, and the Si-face of the substrate was covered by the chiral ligand, leading to Re-attack products with high enantioselectivity (Fig.…”