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. 2018 Dec 19;140(50):17433-17438.
doi: 10.1021/jacs.8b12025. Epub 2018 Dec 10.

Metallaphotoredox-Catalyzed Cross-Electrophile Csp3-Csp3 Coupling of Aliphatic Bromides

Russell T Smith  1 , Xiaheng Zhang  1 , Juan A Rincón  2 , Javier Agejas  2 , Carlos Mateos  2 , Mario Barberis  2 , Susana García-Cerrada  2 , Oscar de Frutos  2 , David W C MacMillan  1
Affiliations

Metallaphotoredox-Catalyzed Cross-Electrophile Csp3-Csp3 Coupling of Aliphatic Bromides

Russell T Smith et al. J Am Chem Soc. .

Abstract

A strategy for the installation of small alkyl fragments onto pharmaceutically relevant aliphatic structures has been established via metallaphotoredox catalysis. Herein, we report that tris(trimethylsilyl)silanol can be employed as an effective halogen abstraction reagent that, in combination with photoredox and nickel catalysis, allows a generic approach to Csp3-Csp3 cross-electrophile coupling. In this study, we demonstrate that a variety of aliphatic drug-like groups can be successfully coupled with a number of commercially available small alkyl electrophiles, including methyl tosylate and strained cyclic alkyl bromides. Moreover, the union of two secondary aliphatic carbon centers, a long-standing challenge for organic molecule construction, has been accomplished with a wide array of structural formats. Last, this technology can be selectively merged with Csp2-Csp3 aryl-alkyl couplings to build drug-like systems in a highly modular fashion.

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Figures

Scheme 1.
Scheme 1.
Small Alkyl Group Installation via Halide Coupling
Scheme 2.
Scheme 2.
Plausible Mechanism for Reductive Methylation
Scheme 3.
Scheme 3.
Iterative Coupling Sequence a Only a small amount (<5%) of homodimerization of the limiting reagent was observed. 1:1 d.r.
See this image and copyright information in PMC

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