Development and Mechanistic Interrogation of Interrupted Chain-Walking in the Enantioselective Relay Heck Reaction

Abstract

The formation of alkyl-palladium complexes via the nucleopalladation of alkenes is the entry point for a wide range of diverse reactions. One possibility is that the intermediate alkyl-Pd complexes can undergo a "chain-walking" event, to allow for remote functionalization through various termination processes. However, there are few methods to selectively interrupt the chainwalking process at a prescribed location. Herein we demonstrate that a variety of homoallylic protected amines undergo an interrupted enantioselective relay Heck reaction to give enantioenriched allylic amine products. The selectivity of this process can be diverted to exclusively yield the ene-amide products by virtue of changing the nature of the amine protecting group. To rationalize this observation, we combine experiment and computation to investigate the mechanism of the chain-walking process and termination events. Isotopic labeling experiments and the computed reaction pathways suggest that the system is likely under thermodynamic control, with the selectivity being driven by the relative stability of intermediates encountered during chain walking. These results illustrate that the chain-walking of alkyl-palladium complexes can be controlled through the alteration of thermodynamic processes and provides a roadmap for exploiting these processes in future reaction development.

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

“…Very recently, Sigman and co‐workers discovered that the protected homoallylic amines could also undergo a relay Heck reaction to deliver enantioselective allylic amines or enamides by adjusting the protecting group of amines and efficiently constructed tetrasubstituted full‐carbon stereocenters (Scheme 37). [ 50 ] Formation of both products was controlled by the stability of the intermediate, which led to the change of termination process of chain‐walking.…”

Palladium-Catalyzed Regioselective Arylation of Unprotected Allylamines

“… 5 − 9 As a result, there are numerous approaches to their synthesis. 10 − 13 A powerful approach for the arylation of olefins is the Mizoroki–Heck (MH) reaction, 14 , 15 though internal olefin substrates often require directing groups to achieve reasonable regioselectivity. 16 − 19 In the case of allylamine substrates, protection of the amine has been required ( Scheme 1 a) to achieve these reactions, 20 − 24 and the reactions are limited to a single arylation except in a few circumstances ( Scheme 1 b).…”

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

“…From a synthetic utility viewpoint, the expansion of scope to a wider range of heterocycles, as well as additional redox acceptors capable of driving the chain migration such as sulfones and sulfonamides, would make this transformation more broadly applicable for the synthesis of bioactive small molecule libraries in drug discovery [73] . Another limitation is the synthesis of quaternary stereocenters, which is currently restrained by the steric hindrance of the alkene substituents [8d, 56] .…”

“…[72] From as ynthetic utility viewpoint, the expansion of scope to aw ider range of heterocycles, as well as additional redox acceptors capable of driving the chain migration such as sulfones and sulfonamides, would maket his transformationm ore broadly applicable for the synthesis of bioactive small molecule libraries in drug discovery. [73] Another limitation is the synthesis of quaternary stereocenters, which is currently restrained by the steric hindrance of the alkene substituents. [8d, 56] It is worth noting that there have been multiple reports on redoxrelay (oxidative) Heck b-functionalization using carbamates as coupling partners; [74] protected alcohols to furnish the corresponding carbonyl products, via in situ deprotections trategies; [61,75] or alkynes to generate C sp -C sp 3 stereocenters.…”