Stepwise Preparation of All-cis 1,3,4-Trifluoro-2-phenylcyclohexane, Avoiding a Phenonium Intermediate

Abstract

The original synthesis of all-cis 1,2,4,5,-tetrafluoro-2-phenylcyclohexane resulted in a trifluorocyclohexene as a significant co-product of the final fluorination step. This product was notable in that an elimination reaction was accompanied by C-F bond formation that had occurred with a retention of configuration. In order to deconvolute this reaction, the two isomers of the ditriflate diol precursor were separated, and they were each treated independently with Et3N·3HF. One gave the original all-cis 1,2,4,5,-tetrafluoro-2-phenylcyclohexane and the other the trifluorocyclohexene. A deuterium labeling experiment was carried out, resulting in a distribution of the isotope in the trifluorocyclohexene consistent with an intermediate (symmetrical) phenonium intermediate. Cognisant of this, a controlled elimination reaction of one of the diastereoisomers with DBU, followed by hydrogenation, gave a cyclohexane triflate, which, on fluorination, gave the all-cis 1,2,3-trifluoro-2-phenylcyclohexane now with an inversion of configuration.

Synthesis of selectively fluorinated cyclohexanes: The observation of phenonium rearrangements during deoxyfluorination reactions on cyclohexane rings with a vicinal phenyl substituent

“…The structure and stereochemistry of product 18 was also confirmed by X-ray structure analysis as shown in Figure 2. In retrospect we can rationalize a rearrangement reaction, which most reasonably proceeded via a phenonium type intermediate as represented by 17 in Scheme 3 [5,[15][16][17][18][19][20]. This is an interesting outcome but not particularly useful for the preparation of a tetrafluorocyclohexyl motif.…”

“…These diols could also be converted to their corresponding triflates 8 and 9. However when the triflates 8 and 9, which could be separated, were treated individually with 3HF.NEt 3 , then 8 gave 1 exclusively, and 9 gave cyclohexene 10 exclusively [5]. The stereochemistry of cyclohexene 10 indicated that the fluorination had occurred with retention of configuration, consistent with a rearrangement via the symmetrical phenonium ion 11 [5].…”

“…We have recently introduced all-cis phenyl-2,3,5,6-tetrafluorocyclohexane 1 as the starting point for the synthesis of a diversity of products 2 carrying a tetrafluorocyclohexyl motif with four fluorine up [1][2][3][4][5][6]. The diversity emerges as the aromatic ring of 1 can be modified by a range of standard electrophilic aromatic substitution reactions [4,6].…”

“…This gives rise to products 2 that contain a unique motif which has four fluorine atoms on one face of a cyclohexane and offers a facially polarized ring, the properties of which appear unique and remain to be fully explored in medicinal and agrochemical discovery programmes. Compound 1 was prepared in a synthesis protocol starting with a Birch reduction of biphenyl 3 to give diene 4 [7][8][9] followed by diepoxidation with mCPBA to generate diepoxide 5 [4,5]. This diepoxide was then treated with 3HF.NEt 3 and converted to inseparable diols 6 and 7.…”

“…This was further supported by a deuterium isotope labelling experiment. [1,5] As part of a programme to extend the structural diversity of the all-cis tetrafluorocyclohexane motifs 2 we were interested in placing a methyl group at the benzylic position to generate products such as 12. To that end we started with the well known modification of the Birch reduction of biphenyl 1 which involves in situ methylation to generate diene 13 [7,9].…”