Abstract
The enantioselective intermolecular C2‐allylation of 3‐substituted indoles is reported for the first time. This directing group‐free approach relies on a chiral Ir‐(P, olefin) complex and Mg(ClO4)2 Lewis acid catalyst system to promote allylic substitution, providing the C2‐allylated products in typically high yields (40–99 %) and enantioselectivities (83–99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2‐allylation, rather than C3‐allylation followed by in situ migration. Steric congestion at the indole‐C3 position and improved π–π stacking interactions have been identified as major contributors to the C2‐selectivity.
Highlights
Indole is a core structural element in many natural and synthetic organic compounds that possess a wide diversity of important biological activities.[1]
We demonstrate the successful implementation of a strategy to access enantioenriched C2-allylated 3substituted[14,15] indoles 3 via the intermolecular allylic substitution of branched allylic alcohols 1 and readily available indoles 2, catalyzed by a chiral Ir-(P, olefin) complex[16] and a Lewis acid additive (Scheme 1 d)
Our investigation started with the identification of suitable reaction conditions, including finding a Lewis acid capable of performing up to three key roles within the allylationmigration cascade: 1) to activate the allylic alcohol towards formation of the Ir–p-allyl complex, 2) to facilitate the enantioselective C2- or C3-allylation whilst avoiding competing N1-allylation, and 3) to facilitate the stereospecific migration of the allyl group from the C3- to the C2-position of indole if needed
Summary
Indole is a core structural element in many natural and synthetic organic compounds that possess a wide diversity of important biological activities.[1]. Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10. 1002/anie.202001956
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