Trifluoromethylthiolation, Trifluoromethylation, and Arylation Reactions of Difluoro Enol Silyl Ethers.

Xingguo Jiang,Denise Meyer,Miguel A Cortés González,Kálmán J Szabó,Dominik Baran

doi:10.1021/acs.joc.0c01030

Abstract

This study reports a new application area of difluoro enol silyl ethers, which can be easily obtained from trifluoromethyl ketones. The main focus has been directed to the electrophilic fluoroalkylation and arylation methods. The trifluoromethylthiolation of difluoro enol silyl ethers can be used for the construction of a novel trifluoromethylthio-α,α-difluoroketone (−COCF2SCF3) functionality. The −CF2SCF3 moiety has interesting properties due to the electron-withdrawing, albeit lipophilic, character of the SCF3 group, which can be combined with the high electrophilicity of the difluoroketone motif. The methodology could also be extended to difluoro homologation of the trifluoromethyl ketones using the Togni reagent. In addition, we presented a method for transition-metal-free arylation of difluoro enol silyl ethers based on hypervalent iodines.

Highlights

Organofluorine compounds have found many important applications in several areas of life sciences
As a part of our organofluorine chemistry program,[19] we sought to expand the reagent scope of difluoro enol silyl ethers (2) to reactions with new types of electrophiles
Many recent efforts have been undertaken to find new methodologies for selective introduction of the SCF3 group.4b,20 This group frequently occurs in drug molecules (e.g., Figure 1f) because of its excellent pharmacochemical properties, such as the strong electron-withdrawing character and an exceptionally high Hansch lipophilicity parameter (π = 1.44).[21]

Summary

Introduction

Organofluorine compounds have found many important applications in several areas of life sciences. The high metabolic stability, ability to modify the lipophilicity, acid−base properties, and overall reactivity/bioavailability of small molecules[1] led to a widespread application of organofluorines especially in medicinal chemistry[2] and agrochemistry.[3] As a consequence, expanding the chemical space of new organofluorine compounds has attracted great attention in industrial and academic research.[4] An important class of druglike molecules is based on α-fluorinated ketone motifs (Figure 1). Due to the strong electron-withdrawing character of di-, tri-, and perfluoro alkyl groups, the electrophilicity of the neighboring keto functionality is enhanced. Nucleophilic functionalities of enzymes, such as the hydroxy group of serine or other residues, readily interact with the low lying π*(C O)

Methods

Results

Conclusion