Enantioselective C2‐Alkylation of Indoles through a Redox‐Relay Heck Reaction of 2‐Indole Triflates

Abstract

A palladium-catalyzed enantioselective redox-relay Heck reaction of 2-indole triflates and disubstituted alkenes is reported. This process combines readily-available indole triflates with a variety of alkenes to afford a range of indole derivatives bearing a stereocenter adjacent to C2. Enantioselectivity is achieved through use of a simple pyridine-oxazoline ligand. Tuning the electronics of the indole, through judicious choice of N-protecting group, is required to ensure selective β-hydride elimination away from the indole core. Utility of this method is highlighted in a modular formal synthesis of an S1P1 agonist precursor developed by Merck.

Recent Advances of Catalytic Enantioselective Heck Reactions and Reductive‐Heck Reactions

“…The desired C2‐alkylated indoles bearing a benzylic chiral stereocenter were achieved in moderate to good yields with good enantioselectivities. [ 44 ] N ‐Protecting group of indole substrate was crucial to the reaction. No product was isolated for N ‐alkylating indole as the alkyl‐Pd(II) intermediate shown in Int‐II preferred to eliminate H a and migrate toward more electronic‐rich indole side instead of the hydroxyl side.…”

Stereoselective Remote Functionalization via Palladium‐Catalyzed Redox‐Relay Heck Methodologies

“…Indoles can be functionalized at the C2-position via ar edoxrelay Heck reaction by use of the correspondingt riflate (Scheme 13). [43] Only ethyl carbamate-protected indoles (44) were successfully utilized, with methyl-, phenyl-or acetyl-protected indoles all resulting in either no product formation or decomposition. All substrates that coupled did so with high enantioselectivity,i ncluding one example with as econdary al-cohol, which led to the formation of the corresponding ketone (47).…”

“…All substrates that coupled did so with high enantioselectivity, including one example with a secondary alcohol, which led to the formation of the corresponding ketone ( 47 ). These C2‐activated indole triflates could also be coupled to ene‐lactams ( 48 ) and disubstituted alkenes containing a remote carbonyl moiety, which results in formation of the corresponding α,β‐unsaturated product ( 49 ), in high enantiomeric ratios [43] …”

“…These C2-activated indole triflates could also be coupled to ene-lactams( 48)a nd disubstituted alkenes containing a remote carbonyl moiety,w hich results in formationo ft he corresponding a,b-unsaturatedp roduct (49), in high enantiomeric ratios. [43]…”

Enantioselective Heck Arylation of Acyclic Alkenol Aryl Ethers: Synthetic Applications and DFT Investigation of the Stereoselectivity

“…Recent developments in the enantioselective Heck arylations have focused mostly on the use of chiral bisphosphine monoxides (BPMO), P , N ‐ligands, N , N ‐ligands, and phase‐transfer chiral counterions, although the popular bidentate phosphines are still commonplace . Additionally, the introduction of selectivity‐inducing strategies, such as the use of redox relay, and directing groups have also greatly improved and extended the scope of this reaction . However, in spite of its tremendous success involving nonactivated and cyclic electron‐rich alkenes, the effective arylation of acyclic electron‐rich alkenes has been lagging behind significantly.…”