Ru-NHC-Catalyzed Asymmetric, Complete Hydrogenation of Indoles and Benzofurans: One Catalyst with Dual Function

Abstract

The highly enantioselective and complete hydrogenation of protected indoles and benzofurans has been developed, affording facile access to a range of chiral three-dimensional octahydroindoles and octahydrobenzofurans, which are prevalent in many bioactive molecules and organocatalysts. Remarkably, we are in control of the nature of the ruthenium N-heterocyclic carbene complex and employed the complex as both homogeneous and heterogeneous catalysts, providing new avenues for its potential applications in the asymmetric hydrogenation of more challenging aromatic compounds.

Figure 1

(a–d) Development of a new synergistic catalytic system using one single molecular complex to access saturated octahydroindoles and octahydrobenzofurans. (e) Representative marketed pharmaceuticals, natural products, and catalysts containing octahydroindole moieties.

Figure 2

Substrate scope of 3-alkyl-protected indoles. General conditions: 1 (0.1 mmol), 4 Å MS (50 mg), and 3 (0.8 mL, 0.025 mmol/mL) in n-hexane (0.2 mL), and the hydrogenation was performed at 25 °C under 100 bar of H₂ for 48 h and then at 100 °C under 100 bar of H₂ for 48 h. Yields of isolated products including all diastereomers are given. The major diastereomer is separable. er was determined by chiral HPLC or chiral GC-FID. dr was determined by GC-FID of the crude product mixture. ^aPhenyl-substituent-containing substrate was used.

Figure 3

Substrate scope of 2-methyl-protected indoles and 2-alkyl-benzofurans. General conditions: 4 (0.1 mmol), 4 Å MS (50 mg), and 3 (0.8 mL, 0.025 mmol/mL) in Et₂O (2.0 mL), and the hydrogenation was performed at 25 °C under 70 bar of H₂ for 48 h and then at 100 °C under 100 bar of H₂ for 48 h. Yields of isolated products including all diastereomers are given. The major diastereomer is inseparable. er was determined by chiral HPLC or chiral GC-FID. dr was determined by GC-FID of the crude product mixture. Reaction condition-based sensitivity assessment (within box).

Figure 4

(a) Gram-scale synthesis of 5a. (b) Diversification of product 5a, synthesizing drug derivative 8c. (c) Protecting group exchange. (d) Organocatalytic application.