Selectively fluorinated cyclohexane building blocks: Derivatives of carbonylated all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane

Palladium catalysed carbonylation reactions using the meta- and para-iodo derivatives of all-cis-3-phenyl-1,2,4,5-tetrafluorocyclohexane (4) are illustrated as the start point for a variety of functional group interconversions. The resultant benzaldehyde and benzoic acids offer novel building blocks for further derivatisation and facilitate the incorporation of the facially polarised all-cis-1,2,4,5-tetrafluorocyclohexane motif into more advanced molecular scaffolds.


1,2-Bis(4-(all-cis-2,3,5,6-tetrafluorocyclohexyl)phenyl)ethane (17)
A solution of TiCl 4 in DCM (1.0 M) (0.45 mL, 0.45 mmol) was added dropwise to a suspension of Zn (30 mg, 0.46 mmol) in anhydrous THF (2 mL) at 0 ºC. The resulting mixture was heated at reflux for 1 h. After cooling to 0 ºC, a solution of aldehyde 15 (40 mg, 0.15 mmol) in anhydrous THF (2 mL) was added, and the reaction was heated at reflux for 16 h. The reaction was then poured into a mixture of a saturated NaHCO 3 (5 mL) solution and DCM (5 mL) and was stirred for 3 h. After filtration through a Celite pad, and washing with hot chloroform, the layers were separated. The aqueous layer was extracted into ethyl acetate and the combined extracts were dried (Na 2 SO 4 ), filtered and the solvent removed.
The product was taken up in ethyl acetate (10 mL) and was directly hydrogenated by addition of Pd/C catalyst (5 mg) and stirred under an atmosphere of hydrogen. The reaction was stirred for 16h at 20 °C and was then filtered through a Celite pad and the solvent evaporated. Purification over silica gel eluting with petrol/ethyl acetate (1:1)

1-(Iodomethyl)-4-(all-cis-2,3,5,6-tetrafluorocyclohexyl)benzene (20)
An aqueous solution of HI (57%) (0.58 mL) was added dropwise to a solution of p-benzyl alcohol 19 (120 mg, 0.45 mmol) in chloroform (5 mL). The mixture was allowed to stir at room temperature for 30 h, and then the excess of iodine was destroyed by adding Na 2 SO 3 solution. The product was extracted into chloroform (2 × 30 mL), and the organics were combined and washed with saturated NaHCO 3 solution and then dried (Na 2 SO 4 ). Filtration and then removal of the organic solvent under reduced pressure gave benzyl iodide 20 as S9 colourless solid. This product was used directly without further purification (163 mg, 95%).

Methyl (S)-2-((tert-butoxycarbonyl)amino)pent-4-ynoate (24)
Thionyl chloride (0.5 mL, 6.5 mmol) was added dropwise over 5 min to dry MeOH (5 mL) at 0 °C and the solution was stirred for 10 min before propargyl-L-glycine was added (200 mg, 1.77 mmol) in one portion. The reaction was stirred for 16 h at 20 °C. The solvent and the excess thionyl chloride were then removed under reduced pressure to give an oily residue.
The residue was dissolved in MeCN (5 mL), and then Et 3 N (0.271 mL, 1.9 mmol) and di-tert-S11 butyl pyrocarbonate (423 mg, 1.9 mmol) were added and the reaction was stirred for 2 h at ambient temperature. The solvent was then evaporated and the resulting residue suspended in 1 M NaHSO 4 (10 mL). The product was extracted into CH 2 Cl 2 (3 × 20 mL) and the combined extracts were washed with saturated NaHCO 3 (5 mL) and dried (Na 2 SO 4 ). The solution was filtered through a Celite pad and was evaporated under reduced pressure to afford the product which was purified over silica gel eluting with (ethyl acetate/petrol) (9:1) to give 27 as a colourless oil (308 mg, 81%).
The solvent was removed and the product purified over silica gel eluting with ethyl acetate/petrol (5:1) to afford the protected amino acid 25 as a white solid (71 mg, 72%).