Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif.

Tetiana Bykova,Alexandra M Z Slawin,Nawaf Al-Maharik,David O'Hagan

doi:10.3762/bjoc.13.72

Tetiana Bykova, Alexandra M Z Slawin + Show 2 more

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https://doi.org/10.3762/bjoc.13.72

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Abstract

This paper reports the synthesis of three amine stereoisomers 5a–c of the tetrafluorocyclohexyl ring system, as building blocks for discovery chemistry programmes. The synthesis starts from a Birch reduction of benzonitrile, followed by an in situ methyl iodide quench. The resultant 2,5-cyclohexadiene was progressed via double epoxidations and then hydrofluorination ring opening reactions. The resultant fluorohydrin moieties were then converted to different stereoisomers of the tetrafluorocyclohexyl ring system, and then reductive hydrogenation of the nitrile delivered three amine stereoisomers. It proved necessary to place a methyl group on the cyclohexane ring in order to stabilise the compound against subsequent HF elimination. The two all-cis tetrafluorocyclohexyl isomers 5a and 5b constitute facially polarized cyclohexane rings, with fluorines on the electronegative face and hydrogens on the electropositive face.

Highlights

The all-cis-2,3,5,6-tetrafluorocyclohexane 1 ring has been introduced recently as a polarized cyclohexane ring and it has been a focus of our research group to elaborate new building blocks that enable the introduction of this motif into organic discovery programmes (Figure 1) [1,2,3]
We have recently demonstrated that both diastereoisomers of alcohols 3 and their corresponding aldehydes 4 (Figure 1), could be prepared after a Birch reduction on benzoic acid, quenching with methyl iodide, and subsequent conversion of the cyclohexadiene product to a tetrafluorocycloheane motif [11]
In this paper we report the preparation of amines of this series starting from a Birch reduction on benzonitrile, and with a similar methyl iodide quench, to generate amines 5, which are stable to hydrogen fluoride elimination

Summary

Introduction

The all-cis-2,3,5,6-tetrafluorocyclohexane 1 ring has been introduced recently as a polarized cyclohexane ring and it has been a focus of our research group to elaborate new building blocks that enable the introduction of this motif into organic discovery programmes (Figure 1) [1,2,3]. We have recently demonstrated that both diastereoisomers of alcohols 3 and their corresponding aldehydes 4 (Figure 1), could be prepared after a Birch reduction on benzoic acid, quenching with methyl iodide, and subsequent conversion of the cyclohexadiene product to a tetrafluorocycloheane motif [11].

Results

Conclusion