Asymmetric C—H Functionalization of Indoles via Enantioselective Protonation

Abstract

Asymmetric C—H functionalization of indoles from Rh2(OAc)4 and chiral phosphoric acid co-catalyzed reactions of aryl diazoacetates with indoles has been investigated. Through mechanistic study regarding to the proton transfer pathway of the C—H functionalization of indoles, a new strategy to achieve the asymmetric C—H functionalization of indoles from metal carbenoids via enantioselective protonation has been proposed. We initially carried out a deuterium isotope experiments in order to obtain more insight into the proton transfer process of the C—H functionalization of indoles, and the experiments indicated an “indirect proton transfer” in the reaction. A proton-transfer shuttle such as H2O was needed to complete the reaction. The observation provides us an opportunity to design a chiral proton-transfer shuttle to achieve the asymmetric C—H functionalization. In this paper, Rh2(OAc)4 catalyzed diazo decomposition of a aryl diazoacetate generates a metal carbenoid. Reaction of the metal carbenoid with an indole at C-3 position generates a zwitterionic intermediate. A bifunctional chiral phosphoric acid serves as a chiral proton shuttle and helps the proton transfer process via an enantioselective protonation to finish the reaction in high yield and enantioselectivity. A number of indoles including N-alkyl, aryl , silyl and a number of α-aryl-α-diazoesters are well tolerated under the established catalytic conditions, providing good to high enantioselectivity (up to 94% ee) in excellent yield (up to 99% yield). A representative procedure for the enantioselective C—H functionalization of indoles is as following: A mixture of 6-chloro-N-methyl indole (1e) (41 mg, 0.25 mmol), transition metal catalyst Rh2(OAc)4 (1 mg, 0.0025 mmol, 1 mol%), chiral phosphoric acid co-catalyst (R)-4j (3.8 mg, 0.005 mmol, 2 mol%) and 4A MS (100 mg) in 1 mL of toluene was stirred at the 0 °C. Methyl phenyldiazo acetate (2a) (53 mg, 0.3 mmol) in 1 mL of toluene was added over 1 h period of time via a syringe pump. After completion of the addition, the reaction was stirred for additional 5 min at the same temperature. Solvent was evaporated under reduced pressure to give corresponding crude product. The crude product was purified by flask chromatography on silica gel (eluent: EtOAc/light petroleum ether, V∶V=1∶ 40~1∶10) to give the pure product 3q in 92% yield with 94% ee.