Abstract
Aryl 2,2,2-trifluoroethyl sulfides were synthesized by copper(I)-catalyzed nucleophilic aromatic substitution reaction (Goldberg-Ullmann coupling). The method requires aryl iodides and 2,2,2-trifluoroethyl thioacetate as starting materials, benzylamine as solvent and base, and copper(I) bromide as a catalyst. The reaction mixture was stirred at 110 °C for 6 h under inert atmosphere to afford the targeted aryl 2,2,2-trifluoroethyl sulfides in moderate to good yield.
Highlights
The unique properties of fluorine [1] have been exploited for the development of novel and effective biochemical tools and therapeutic agents, including active pharmaceutical ingredients (API’s) as well
The fact that a large number of fluorine-containing agents have been approved by the US Food and Drug Administration (FDA) for medical use clearly demonstrates the importance of fluorine in drug discovery and development [4]
We present a copper-catalyzed aromatic nucleophilic substitution method (Goldberg-Ullmann coupling) for the synthesis of aryl 2,2,2-trifluoroethyl sulfides at multigram scale using simple reaction conditions
Summary
The unique properties of fluorine [1] have been exploited for the development of novel and effective biochemical tools and therapeutic agents, including active pharmaceutical ingredients (API’s) as well. In the past three decades the extraordinary potential of fluorine-containing biologically relevant molecules has been explored in medicinal chemistry [2], chemical biology, pharmacology, drug discovery and development [3], as well as in diagnostic and therapeutic applications. Fluorine is recognized as the second favorite heteroatom in current drug design, after nitrogen. Following this paradigm, e.g. the replacement of a CeH or CeO bond with a CeF bond in biologically active compounds frequently introduce beneficial properties such as higher metabolic stability, increased binding affinity to target proteins, and increased membrane permeability [5]. Special attention is called on the potential of the development of sulfur-fluorine overlap pharmaceuticals, where polarity tuning of the target molecule is enabled by the changing the valences of the sulfur fragments (e.g. S, SO, SO2) in the fluoro-organosulfur compounds [8]
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