Rhodium-catalysed C(sp(2))-C(sp(2)) bond formation via C-H/C-F activation.

Panpan Tian,Teck-Peng Loh,Chao Feng

doi:10.1038/ncomms8472

Abstract

Fluoroalkenes represent a class of privileged structural motifs, which found widespread use in medicinal chemistry. However, the synthetic access to fluoroalkenes was much underdeveloped with previous reported methods suffering from either low step economy or harsh reaction conditions. Here we present a RhIII-catalysed tandem C–H/C–F activation for the synthesis of (hetero)arylated monofluoroalkenes. The use of readily available gem-difluoroalkenes as electrophiles provides a highly efficient and operationally simple method for the introduction of α-fluoroalkenyl motifs onto (hetero)arenes under oxidant-free conditions. Furthermore, the employment of alcoholic solvent and the in-situ generated hydrogen fluoride are found to be beneficial in this transformation, indicating the possibility of the involvement of hydrogen bond activation mode with regards to the C–F bond cleavage step.

Highlights

Fluoroalkenes represent a class of privileged structural motifs, which found widespread use in medicinal chemistry
The incorporation of fluorine or fluorine-containing structural motifs into organic molecule brings about substantial improvement in its bioactivity and provides unique chemical and physical properties, enabling the widespread use of this strategy in the field of medicinal chemistry[3,4,5]
After examination of a considerable variety of reaction parameters, we were rather pleased to find that the anticipated fluoroalkenylation product could be obtained in 89% yield when using [RhCp*(CH3CN)3](SbF6)[2] as the catalyst and methanol as solvent, and at 80 °C for 16 h

Summary

Introduction

Fluoroalkenes represent a class of privileged structural motifs, which found widespread use in medicinal chemistry. The development of a Rh(III)-catalysed C–H functionalization protocol that enables the easy access of biologically relevant fluoroalkenes is highly desirable and the feasibility of such protocol was based on the following considerations: (i) Rh(III)-catalysed alkenylation has evolved to be a competent and reliable method for the introduction of olefin segments, stoichiometric amount of external oxidant was always required to fulfill the redox demand (Fig. 1a)[33,34]; (ii) notwithstanding its high dissociation energy, the C–F bond could be activated by transition metal or through the formation of hydrogen bond, provided that suitable hydrogen bond donor is present (Fig. 1b)[35,36,37,38,39,40]; (iii) gem-difluoroalkenes represent a class of appealing synthetic intermediates with the C–C double bond being highly polarized because of the electronegativity of fluorine and the repulsion effect stemming from its unpaired electrons[41,42] It is well-known that heteronucleophiles could undergo facile nucleophilic addition or substitution reactions under basic conditions (Fig. 1c)[43,44,45,46]. With our ongoing interest in rhodium and fluorine chemistry[47,48,49], we would like to present the chelation-assisted C–H activation strategy for the direct incorporation of the a-fluoroalkenyl unit using gem-difluoroalkene as the fluoroalkene donor (Fig. 1e)[50]

Methods

Results

Conclusion