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. 2024 Sep 19;15(42):17685-17690.
doi: 10.1039/d4sc03430a. Online ahead of print.

Copper catalyzed benzylic sp3 C-H alkenylation

Ting-An Chen  1   2 , Richard J Staples  2 , Timothy H Warren  2
Affiliations

Copper catalyzed benzylic sp3 C-H alkenylation

Ting-An Chen et al. Chem Sci. .

Abstract

The prenyl group is present in numerous biologically active small molecule drugs and natural products. We introduce benzylic C-H alkenylation of substrates Ar-CH3 with alkenylboronic esters (CH2)3O2B-CH[double bond, length as m-dash]CMe2 as a pathway to form prenyl functionalized arenes Ar-CH2CH[double bond, length as m-dash]CMe2. Mechanistic studies of this radical relay catalytic protocol reveal diverse reactivity pathways exhibited by the copper(ii) alkenyl intermediate [CuII]-CH[double bond, length as m-dash]CMe2 that involve radical capture, bimolecular C-C bond formation, and hydrogen atom transfer (HAT).

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (a) Prenylated natural products and drug molecules. (b) Prenylation via cross-coupling. (c) sp3 C–H styrenylation. (d) Net prenylation via benzylic C–H alkenylation.
Fig. 2
Fig. 2. (a) Radical relay mechanism for C–H functionalization. (b) β-Diketiminato copper(ii) intermediates in C–H alkynylation, arylation and methylation. (c) Proposed copper(ii) alkenyl intermediate for C–H alkenylation.
Scheme 1
Scheme 1. Size of alkenylboronic ester impacts alkenylation yield.
Fig. 3
Fig. 3. (a) Reversible binding of 2a to [CuI] catalyst in benzene, (b) X-ray structure of alkenylboronic ester adduct, and (c) van't Hoff plot.
Fig. 4
Fig. 4. Reaction of [Cl2NN]Cu-OtBu and 2a (a) in C6H5F, (b) in the presence of Gomberg's dimer in C6H5F, and (c) in toluene. +isolated yield.
Fig. 5
Fig. 5. DFT calculation of (a) [CuI] binds to alkenes, 2a and 3a. (b) spin density plot of [CuII]-CHCMe2. (c) Possible reaction pathways for [CuII]-CHCMe2. Free energies in kcal mol−1 at 298.15 K. For more details, see Schemes S3 and S4.
Scheme 2
Scheme 2. Catalytic cycle for sp3 C–H alkenylation with competing pathways via the [CuII]-CHCMe2 intermediate.
See this image and copyright information in PMC

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