Copper(I)-catalyzed asymmetric 1,6-conjugate allylation

Abstract

Catalytic asymmetric conjugate allylation of unsaturated carbonyl compounds is usually difficult to achieve, as 1,2-addition proceeds dominantly and high asymmetric induction is a challenging task. Herein, we disclose a copper(I)-NHC complex catalyzed asymmetric 1,6-conjugate allylation of 2,2-dimethyl-6-alkenyl-4H-1,3-dioxin-4-ones. The phenolic hydroxyl group in NHC ligands is found to be pivotal to obtain the desired products. Both aryl group and alkyl group at δ-position are well tolerated with the corresponding products generated in moderate to high yields and high enantioselectivity. Moreover, both 2-substituted and 3-substituted allylboronates serve as acceptable allylation reagents. At last, the synthetic utility of the products is demonstrated in several transformations by means of the versatile terminal olefin and dioxinone groups.

Fig. 1. Prior arts in catalytic asymmetric conjugate allylation and our work.

a Failed copper(I)-catalyzed asymmetric conjugate allylation. b Reported catalytic asymmetric conjugate allylation. c This work: copper(I)-catalyzed asymmetric conjugate 1,6-allylation.

Fig. 2. Substrate scope of (E)-2,2-dimethyl-6-alkyl-4H-1,3-dioxin-4-ones in the 1,6-conjugate allylation^a.

Various aliphatic substituents at δ-position are studied.

Fig. 3. Substrate scope of (E)-2,2-dimethyl-6-aryl-4H-1,3-dioxin-4-ones in the 1,6-conjugate allylation^a.

Various aromatic substituents at δ-position are studied.

Fig. 4. Preliminary investigation of 1,6-conjugate allylation with 2-substituted allylboronates (6–8)^a.

Both aromatic and aliphatic substituents at δ-position are tried.

Fig. 5. Diastereoselective 1,6-conjugate allylation.

a The 1.6-conjugate allylation with (E)-allylBPin. b The 1,6-conjugate allylation with (Z)-allylBPin.

Fig. 6. Control experiments with different NHC-ligands.

The importance of the presence of a phenol group in NHC-ligands is demonstrated.

Fig. 7. Transformations of product 5d.

a Ir-catalyzed hydroboration. [Ir(COD)Cl]₂ (5 mol %), dppm (Ph₂PCH₂PPh₂) (10 mol %), HBPin (2 equiv), CH₂Cl₂, rt. b Olefin Metathesis. Hoveyda-Grubbs II catalyst (10 mol %), 4-methylstyrene (2 equiv), CH₂Cl₂, 40 °C. c Transformation to β-keto-ester. MeOH, K₂CO₃, rt. d Transformation to α,β-unsaturated ester. (1) NaBH₄, MeOH, 0 °C; (2) MsCl, Et₃N, CH₂Cl₂, 0 °C to rt. e Transformation to pyrazole. NH₂NH₂•HCl (2 equiv), MeOH, reflux.