N-Heterocyclic carbene-catalyzed enantioselective hetero-[10 + 2] annulation

Abstract

Higher-order cycloadditions are a powerful strategy for the construction of polycycles in one step. However, an efficient and concise version for the induction of asymmetry is lacking. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and could be an ideal choice for enantioselective higher-order cycloadditions. Here, we report an enantioselective [10 + 2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields, and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory calculations provide an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.

Fig. 1. NHC-catalyzed normal and higher-order cycloaddition.

a NHC-catalyzed normal order cycloaddition. b NHC-catalyzed high order cycloaddition. c NHC-catalyzed higher-order cycloaddition (this work).

Fig. 2. Scope of ketones.

Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), cat. F (15 mol%), additive H (5 mol%), PhCO₂Na (0.20 mmol) and DQ (0.22 mmol), hexane (2.0 mL), room temperature, 4 Å MS (60 mg), Ar, 36–96 h.

Fig. 3. Scope of indole-2-carbaldehydes 1.

Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), cat. F (15 mol%), additive H (5 mol%), PhCO₂Na (0.20 mmol) and DQ (0.22 mmol), hexane (2.0 mL), room temperature, 4 Å MS (60 mg), Ar, 36–96 h. ^bDCM-Hexane (1:5) was used.

Fig. 4. Postulated mechanistic pathways.

Postulated catalytic mechanism of [10 + 2] annulation.

Fig. 5. Plot of initial rates vs catalyst and substrates.

a Plot of initial rates vs. catalyst concentrations. b Plot of initial rates vs. 1a concentrations. c Plot of initial rates vs. 2a concentrations. d Plot of initial rates vs. DQ concentrations.

Fig. 6. The DFT investigation on the enantioselectivity of the [10 + 2] annulation.

a The two transition states of TS(II–III)R and TS(II–III)S Gibbs free energy barriers and distortion energies comparing. b NCI analysis of the TS(II–III)R and TS(II–III)S. c The IRC of transition state TS(II)R.

Fig. 7. Gram scale synthesis and transformation.

a Reaction conditions: 1e (4.0 mmol), 2a (4.8 mmol), F (0.60 mmol), DQ (4.4 mmol), additive H (0.20 mmol), PhCO₂Na (4.0 mmol), Hexane (33.4 mL) and DCM (6.6 mL), room temperature, 4 Å M.S. (600 mg), Ar, 40 h. b Reaction conditions: 3d (0.05 mmol), 5 (0.10 mmol), K₂CO₃ (0.10 mmol) and Pd(PPh₃)₄ (0.005 mmol), toluene (0.5 mL), 80 °C, 18 h.