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. 2023 Aug 9;145(31):17023-17028.
doi: 10.1021/jacs.3c07313. Epub 2023 Jul 26.

Electrochemical Nickel-Catalyzed C(sp3)-C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates

Malek Y S Ibrahim  1   2 , Graham R Cumming  3 , Raquel Gonzalez de Vega  1   4 , Pablo Garcia-Losada  3 , Oscar de Frutos  3 , C Oliver Kappe  1   2 , David Cantillo  1   2
Affiliations

Electrochemical Nickel-Catalyzed C(sp3)-C(sp3) Cross-Coupling of Alkyl Halides with Alkyl Tosylates

Malek Y S Ibrahim et al. J Am Chem Soc. .

Abstract

Formation of new C(sp3)-C(sp3) bonds is a powerful synthetic tool to increase molecular diversity, which is highly sought after in medicinal chemistry. Traditional generation of carbon nucleophiles and more modern cross-electrophile-coupling methods typically lack sufficient selectivity when cross-coupling of analogous C(sp3)-containing reactants is attempted. Herein, we present a nickel-catalyzed, electrochemically driven method for the coupling of alkyl bromides with alkyl tosylates. Selective cross-coupling transformations were achieved even between C(sp3)-secondary bromides and tosylates. Key to achieve high selectivity was the combination of the tosylates with sodium bromide as the supporting electrolyte, gradually generating small amounts of the more reactive bromide by substitution and ensuring that one of the reaction partners in the nickel-catalyzed electroreductive process is maintained in excess during a large part of the process. The method has been demonstrated for a wide range of substrates (>30 compounds) in moderate to good yields. Further expanding the scope of electroorganic synthesis to C(sp3)-C(sp3) cross-coupling reactions is anticipated to facilitate the switch to green organic synthesis and encourage future innovative electrochemical transformations.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Challenges in C(sp3)–C(sp3) Cross-Electrophile Coupling
Scheme 2
Scheme 2. Scope of the Electrochemical Cross-Coupling of Alkyl Tosylates with Alkyl Bromides
Conditions A: 3 mL volume, 0.1 M NaBr, 1.3 equiv alkyl bromide, 600 rpm, under Ar. Conditions B: same as conditions A with 0.075 M NaBr and 2 equiv alkyl bromide. GC-FID yield using biphenyl as internal standard. Isolated yields are shown.
Figure 1
Figure 1
(a) Monitoring of the reaction mixture during the cross-coupling of 1a with 1b (Table 1, entry 1). (b) Control experiment using bromide 1f instead of tosylate 1a.
Figure 2
Figure 2
Proposed mechanism for electrochemical cross-coupling.
See this image and copyright information in PMC

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