Cu and Hydroquinone for the Trifluoromethylation of Unprotected Phenols

Jakob Pletz,Walter Goessler,Christoph Koeberl,Michael Fuchs,Wolfgang Kroutil,Oliver Steiner

doi:10.1002/ejoc.201801111

Abstract

Fluorination and trifluoromethylation are indispensable tools in the preparation of modern pharmaceuticals and APIs. Herein we present a concept for the introduction of a trifluoromethyl group into unprotected phenols employing catalytic copper(I) iodide and hydroquinone, tBuOOH, and the Langlois' reagent. The method proceeds under mild conditions and exhibits an extended substrate scope compared to the biocatalytic trifluoromethylation using laccase from Agaricus bisporus. Various functional groups such as aldehydes, esters, ethers, ketones and nitriles were tolerated. The hydroquinone‐mediated trifluoromethylation reaction allowed accessing trifluoromethylated phenols, which are cumbersome to prepare via previously known chemical methods.

Highlights

The introduction of fluoroalkyl-groups (e.g. CF3, CHF2, CH2F, etc.) into organic molecules has become a major topic in various areas of research, in particular medicinal chemistry and drug discovery.[1,2,3] The presence of highly stable C–F bonds increases metabolic stability, membrane permeability or the binding affinity compared to the non-fluorinated congeners.[4]
We recently reported the first biocatalyst dependent trifluoromethylation of unprotected phenols that employs laccase from Agaricus bisporus and trifluoromethylsulfinate salt as the CF3-radical source (Scheme 1d),[29] giving access to building blocks that are difficult and cumbersome to prepare via other methodologies.[19,20,28,29,30,31]
Based on the early reports from Langlois, who used catalytic Cu(SO2CF3)2, NaSO2CF3 and TBHP for the CF3-radical formation for the trifluoromethylation of arenes, we investigated whether and how free copper ions contribute to the observed reactivity of the laccase in the trifluoromethylation.[26]

Summary

Introduction

The introduction of fluoroalkyl-groups (e.g. CF3, CHF2, CH2F, etc.) into organic molecules has become a major topic in various areas of research, in particular medicinal chemistry and drug discovery.[1,2,3] The presence of highly stable C–F bonds increases metabolic stability, membrane permeability or the binding affinity compared to the non-fluorinated congeners.[4]. The addition of 200 μM (0.004 equiv.) CuI restored the activity of the desalted laccase solution and a yield of 48 % was detected at 80 % conversion (Table 1, entry 4). HQ (53 %) corresponds well with the yield of the optimized laccase-catalyzed system (50 %, Table 1, entry 2).[29] In general, HQ only showed a beneficial effect on the product yield in the concentration range between 0.1 equiv.

Results

Conclusion