Asymmetric C-H Functionalization of Indoles via Enantioselective Protonation

Asymmetric C-H functionalization of indoles from Rh-2(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, Rh-2(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 alpha-aryl-alpha-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 Rh-2(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 4 angstrom MS (100 mg) in 1 mL of toluene was stirred at the 0 degrees 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 similar to 1 : 10) to give the pure product 3q in 92% yield with 94% ee.