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. 2024 Nov 20;146(46):31982-31991.
doi: 10.1021/jacs.4c11888. Epub 2024 Nov 6.

Overcoming Copper Reduction Limitation in Asymmetric Substitution: Aryl-Radical-Enabled Enantioconvergent Cyanation of Alkyl Iodides

Su Chen  1 , Decai Ding  1 , Lingfeng Yin  1 , Xiao Wang  1 , Jeanette A Krause  1 , Wei Liu  1
Affiliations

Overcoming Copper Reduction Limitation in Asymmetric Substitution: Aryl-Radical-Enabled Enantioconvergent Cyanation of Alkyl Iodides

Su Chen et al. J Am Chem Soc. .

Abstract

Cu-catalyzed enantioconvergent cross-coupling of alkyl halides has emerged as a powerful strategy for synthesizing enantioenriched molecules. However, this approach is intrinsically limited by the weak reducing power of copper(I) species, which restricts the scope of compatible nucleophiles and necessitates extensive ligand optimization or the use of complex chiral scaffolds. To overcome these challenges, we introduce an aryl-radical-enabled strategy that decouples the alkyl halide activation step from the chiral Cu center. We demonstrate that merging aryl-radical-enabled iodine abstraction with Cu-catalyzed asymmetric radical functionalization enables the conversion of racemic α-iodoamides to enantioenriched alkyl nitrile products with good yield and enantioselectivity. The rational design of chiral ligands identified a new class of carboxamide-containing BOX ligands. Mechanistic studies support an aryl-radical-enabled pathway and the unique hydrogen-bonding ability in the newly designed BOX ligands. This aryl-radical-enabled asymmetric substitution reaction has the potential to significantly expand the scope of Cu-catalyzed enantioconvergent cross-coupling reactions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Development of aryl-radical-enabled, Cu-catalyzed enantioconvergent cross-coupling of alkyl halides.
Figure 2.
Figure 2.
Development of Cu-catalyzed, aryl-radical-enabled, enantioconvergent cyanation of alkyl iodides. (a) The proposed catalytic cycle. (b) Initial results using commercially available BOX ligands. (c) Design new BOX-type ligands by installing hydrogen bonding sites. (d) Reaction optimization with ScBOX chiral ligands: reactions were conducted at 0.2 mmol. Yield determined by 1H NMR using dibromomethane as the internal standard. e.e. determined by HPLC with chiral stationary phase.
Figure 3.
Figure 3.
Synthetic application of the aryl-radical-enabled, Cu-catalyzed enantioconvergent cyanation reaction. Enantiospecificity (e.s.) is defined as e.e.product/e.e.reactant. Ar = 2-bromophenyl.
Figure 4.
Figure 4.
Mechanistic studies of the aryl-radical-enabled enantioconvergent cyanation reaction. (a) Ring-opening studies support the involvement of alkyl radicals, Ar = 2-bromophenyl; (b) Formation of mesityl iodide supports the formation of mesityl radical; (c) alkyl iodide remained racemic during the reaction; (d) The hydrogen bonding ability of the ScBOX is shown by crystal structure; (e) a possible stereochemical model that explains the observed enantioselectivity. Ad = 1-adamantyl.
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