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. 2020 Aug 7;10(15):8315-8320.
doi: 10.1021/acscatal.0c02950. Epub 2020 Jul 17.

Nickel-Catalyzed Decarbonylative Synthesis of Fluoroalkyl Thioethers

Conor E Brigham  1 , Christian A Malapit  1 , Naish Lalloo  1 , Melanie S Sanford  1
Affiliations

Nickel-Catalyzed Decarbonylative Synthesis of Fluoroalkyl Thioethers

Conor E Brigham et al. ACS Catal. .

Abstract

This report describes the development of a nickel-catalyzed decarbonylative reaction for the synthesis of fluoroalkyl thioethers (RFSR) from the corresponding thioesters. Readily available, inexpensive, and stable fluoroalkyl carboxylic acids (RFCO2H) serve as the fluoroalkyl (RF) source in this transformation. Stoichiometric organometallic studies reveal that RF-S bond-forming reductive elimination is a challenging step in the catalytic cycle. This led to the identification of diphenylphosphinoferrocene as the optimal ligand for this transformation. Ultimately, this method was applied to the construction of diverse fluoroalkyl thioethers (RFSR), with R = both aryl and alkyl.

Keywords: Nickel-catalysis; decarbonylation; fluoroalkyl carboxylic acids; fluoroalkylation; thioether synthesis.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
(A) Representative examples of bioactive molecules containing fluoroalkyl thioethers (RFSR). (B) Existing synthetic approaches to RFSR (i, ii) and our approach (iii).
Figure 2.
Figure 2.
(A) Example of precedent for decarbonylative thioetherification. (B) Proposed catalytic cycle. (C) Initial catalysis studies. (D) Stoichiometric studies with PnBu3 as ligand.
Figure 3.
Figure 3.
(A) Stoichiometric and (B) catalytic studies with dppf.
Figure 4.
Figure 4.
Scope of (A) aryl and (B) alkyl thioethers. a% conversion of 1 to 2 as determined by 19F NMR spectroscopy. bY-ield determined by 19F NMR spectroscopy with 4–fluorotoluene as internal standard. cCatalyst loading was increased to 15 mol% Ni(cod)2, 18 mol% dppf.
Figure 5.
Figure 5.
Scope of fluoroalkyl groups derived from commercial RFCO2H. Isolated yields. See the SI for details. aCatalyst loading was increased to 20 mol% Ni(cod)2 and ligand was Xantphos (24 mol %).
See this image and copyright information in PMC

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