# Enantioselective Reductive Alkenylation of α‐CF2H (‐CF3) Amino Halides: Rapid Access to Chiral α‐CF2H (‐CF3) Allylamines

## TL;DR

This paper introduces a new method to create chiral molecules with fluoroalkyl groups, which are important in drug development.

## Contribution

A Ni-catalyzed enantioselective reductive alkenylation method for constructing stereocenters with α-CF2H or CF3 groups.

## Key findings

- The method uses arylamide moieties to stabilize fluoroalkyl radical intermediates.
- It achieves excellent enantio- and chemoselectivity under mild conditions.
- The approach allows late-stage functionalization with broad substrate scope.

## Abstract

The incorporation of fluoroalkyl groups into drug candidates has garnered increasing attention in the pharmaceutical industry due to their ability to modulate lipophilicity, permeability, metabolic stability, and binding affinity. Despite significant advances realized, the means to introducing fluoroalkyl groups such as ─CF2H or ─CF3 in an enantioselective manner remain scarce. Herein, we report a Ni‐catalyzed enantioselective reductive alkenylation of α‐CF2H or ─CF3 amino chlorides with vinyl iodides. This method provides an efficient and modular technique for constructing stereocenters bearing a fluoroalkyl group. A key to success was the incorporation of an arylamide moiety with the substrates, which stabilizes the α‐fluoroalkyl radical intermediate, thus offering a de novo approach to access enantioenriched α‐CF2H (─CF3) allylamines. Our protocol is characterized by its mild reaction conditions, broad substrate scope, as well as excellent enantio—and chemo‐selectivity, even in the context of late‐stage functionalization.

Difluoromethyl (CF2H) group, the bioisostere of hydroxyl thiol methyl or amide is privileged in medicinal chemistry due to hydrogen‐binding ability and lipophilic, metabolically stable, and chemical inert nature. However, enatioseleceive CF2H introduction remains challenging. We report a modular approach for the constructing stereocenters bearing CF2H or CF3 groups via Ni‐catalyzed asymmetric reductive alkenylation of α‐CF2H or ‐CF3 amino chlorides with vinyl iodides.