Cyclohexanemethanol, 4,4-difluoro- (9CI)

Under nitrogen atmosphere, at 0 °C, to a suspension of LiA1H4 (2.0 M THF solution, 11.2 mL, 22.47 mmol) in dry Et20 (55 mL), methyl 4, 4-difluorocyclohexane carboxylate (1.0 g, 5.62 mmol) in dry Et20 (10 mL) was added dropwise. The resulting reaction mixture was stirredat r.t. for 1 h, and then cooled to 0 °C. H20 (1.0 mL) was slowly and cautiously added, followedby 3.0 M KOH solution (1.0 mL) and additional H20 (4.5 mL). The mixture was stirred at 0 °Cfor 1 h and then filtered off. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (0.68 g, 81percent), which was used in the next step without any further purification. ‘H NMR (DMSO-d6): ö 4.51 (t, 1H, J= 5.6 Hz), 3.26 (t, 2H, J= 7.5 Hz), 2.05-1.93 (m, 2H), 1.86-1.66 (m, 4H), 1.55-1.41 (m, 1H), 1.21-1.08 (m, 2H).Under nitrogen atmosphere, at 0 °C, to a suspension of LiAlH4 (2.0 M THF solution, 11.2 mL, 22.47mmol) in dry Et2O (55 mL), methyl 4, 4-difluorocyclohexane carboxylate (1.0 g, 5.62 mmol) in dryEt2O (10 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for1 h, and then cooled to 0 °C. H2O (1.0 mL) was slowly and cautiously added, followed by 3.0 M KOHsolution (1.0 mL) and additional H2O (4.5 mL). The mixture was stirred at 0 °C for 1 h and thenfiltered off. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, affordingthe title compound (0.68 g, 81percent), which was used in the next step without any further purification. 1HNMR (DMSO-d6): δ 4.51 (t, 1H, J = 5.6 Hz), 3.26 (t, 2H, J = 7.5 Hz), 2.05–1.93 (m, 2H), 1.86–1.66(m, 4H), 1.55–1.41 (m, 1H), 1.21–1.08 (m, 2H).4, 4-Difluoro-cyclohexanecarboxylate (500 mg, 2.60 mmol) was dissolved in tetrahydrofuran (15 mL), and lithium aluminum hydride (1.48 g, 3.90 mmol) was added in batches at 0°C, and stirred to react for 18 hours under nitrogen atmosphere. To a solution of ethyl 4-oxocyclohexanecarboxylate 13 (880 mg, 5.17 mmol) in 0H2012(15 mL)was added diethylaminosulfurtrifluoride(1.368mL, 10.35 mmol) at0°C. Theresulting mixture was stirred for 24 h at 23 0 before it was quenched with a saturated solution of NaHCO3 (20 mL). The resulting mixture was extracted with 0H2012 (4 x 10mL), the combined organic layers were dried over Na2504 and concentrated in vacuo to afford the corresponding gem-difluoro- and vinyl fluoride as an inseparable mixture. Theresidue was passed through a short silica plug (EtOAc) and concentrated in vacuo prior to use.To a CH2CI2 solution of the mixture of gem-difluoro- and vinyl fluoride at 23 00 was added3-chloroperbenzoic acid (1.158 g, 5.17 mmol, 77percent in H20). The resulting reaction mixturewas stirred for 16 h at 23 00 before it was quenched with a saturated solution of Na2SO3(10 mL). The resulting mixture was extracted with CH2CI2 (4 x 10 mL), the combinedorganic layers were dried over Na2SO4 and concentrated in vacuo to give a crude mixtureof gem-difluoride and fluoroepoxide. This mixture which was re-dissolved in THF (10 mL) and lithium aluminium hydride (392 mg, 10.33 mmol) was added at 0 c The resulting reaction mixture was stirred for 4 h at 0°C before it was diluted with Et20 (10 mL) and slowly quenched with H20 (0.5 mL) followed by NaOH (0.5 mL, 15percent aq.). The mixturewas stirred for further 30 mm at 2300 before it was filtered. The filtration cake was washed with Et20 (2 x 10 mL) and the combined filtrate concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexanes:EtOAc 3:1 —* 1:1) to afford compound 14 (480 mg, 62percent for 3 steps) as a pale yellow oil.1H NMR (400 MHz, ODd3) O = 3.47 (d, J= 8.0 Hz, 2 H), 2.25—1.97 (m, 3 H), 1.86—1.47 (m, 5 H), 1.33—1.15 (m, 2 H); 19F NMR (376 MHz, 0D013) O = -91.35 (d, J= 235.3 Hz, 1 F), -102.01 (dtt, J= 235.3, 32.4, 10.0 Hz, 1 F).To a solution of 106 (4.00 g, 20.8 mmol) in THF (40 mL) was added LiAIH4 (1.18 g, 31.2 mmol) inportions at 0 C. The mixture was stirred at25 C for4 h. The mixture was cooled to 0 C andquenched by saturated solution of potassium sodium tartrate (3 mL) the precipitate formed was collected, filtered and concentrated in vacuo to give 107 (2.6 g, 83percent) as a colorless oil. 1H NMR (400 MHz, CDCI3) 3.45 (J = 4.0 Hz, 2H), 2.07-2.03 (m, 2H), 2.01-1.83 (m, 2H), 1.82-1.79 (m, 2H), 1.72-1.64 (m, 1H), 1.28-1.24 (m, 2H).

Molecular Weight:150.17
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:150.08562133
Monoisotopic Mass:150.08562133
Topological Polar Surface Area:20.2
Heavy Atom Count:10
Complexity:104
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes