4-fluorooxane-4-carbaldehyde

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 6-bromopyridin-2-amine (3.03 g, 17.50 mmol) was added the crude solution of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde in DCM. To the mixture was added acetic acid (1.002 mL, 17.50 mmol) and sodium triacetoxyborohydride (5.56 g, 26.3 mmol) in portions. The mixture was stirred for 2 hr at ambient temperature. The mixture was diluted carefully with saturated aqueous NaHCO3 solution. The separated aqueous layer was extracted with DCM (1×). The combined organic layers were washed with water (1×), saturated aqueous NaHCO3 solution (1×) and concentrated in vacuo. The solid resulting residue was dissolved in DCM (100 mL) and 3M aqueous HCl (60 mL). The separated organic layer was extracted with 3M aqueous HCl (3×20 mL). The combined acidic layers were washed with DCM (1×). Solid NaHCO3 was added carefully to the acidic solution [Caution: gas development!] until pH>˜8. The aqueous mixture was extracted with DCM (2×) and EtOAc (2×). The combined organic layers were concentrated in vacuo. The resulting residue was dissolved in EtOAc. The solution was washed with 0.3M aqueous HCl, and brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane= 5/95 for 3 min, then EtOAc/heptane= 5/95 to 30/70 over 15 min, then EtOAc/heptane= 30/70] providing 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 1.82 g. LCMS (m/z): 288.9/291.0 [M+H]+; Retention time=0.84 min. The separated aqueous layer was extracted with DCM (1×) The combined organic layers were washed with water (1×), saturated aqueous NaHCO3 solution (1×) concentrated in vacuo The solid resulting residue The separated organic layer was extracted with 3M aqueous HCl (3×20 mL) The combined acidic layers were washed with DCM (1×) Solid NaHCO3 was added carefully to the acidic solution [Caution: gas development!] until pH>˜8 The aqueous mixture was extracted with DCM (2×) and EtOAc (2×) The combined organic layers were concentrated in vacuo The resulting residue was dissolved in EtOAc The solution was washed with 0.3M aqueous HCl, and brine dried over Na2SO4 filtered off concentrated in vacuo The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane= 5/95 for 3 min EtOAc/heptane= 5/95 to 30/70 over 15 min

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 6-bromopyridin-2-amine (3.03 g, 17.50 mmol) was added the crude solution of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde in DCM. To the mixture was added acetic acid (1.002 mL, 17.50 mmol) and sodium triacetoxyborohydride (5.56 g, 26.3 mmol) in portions. The mixture was stirred for 2 hr at ambient temperature. The mixture was diluted carefully with saturated aqueous NaHCO3 solution. The separated aqueous layer was extracted with DCM (1×). The combined organic layers were washed with water (1×), saturated aqueous NaHCO3 solution (1×) and concentrated in vacuo. The solid resulting residue was dissolved in DCM (100 mL) and 3M aqueous HCl (60 mL). The separated organic layer was extracted with 3M aqueous HCl (3×20 mL). The combined acidic layers were washed with DCM (1×). Solid NaHCO3 was added carefully to the acidic solution [Caution: gas development!] until pH>˜8. The aqueous mixture was extracted with DCM (2×) and EtOAc (2×). The combined organic layers were concentrated in vacuo. The resulting residue was dissolved in EtOAc. The solution was washed with 0.3M aqueous HCl, and brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=5/95 for 3 min, then EtOAc/heptane=5/95 to 30/70 over 15 min, then EtOAc/heptane=30/70] providing 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 1.82 g. LCMS (m/z): 288.9/291.0 [M+H]+; Retention time=0.84 min. The separated aqueous layer was extracted with DCM (1×) The combined organic layers were washed with water (1×), saturated aqueous NaHCO3 solution (1×) concentrated in vacuo The solid resulting residue The separated organic layer was extracted with 3M aqueous HCl (3×20 mL) The combined acidic layers were washed with DCM (1×) Solid NaHCO3 was added carefully to the acidic solution [Caution: gas development!] until pH>˜8 The aqueous mixture was extracted with DCM (2×) and EtOAc (2×) The combined organic layers were concentrated in vacuo The resulting residue was dissolved in EtOAc The solution was washed with 0.3M aqueous HCl, and brine dried over Na2SO4 filtered off concentrated in vacuo The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=5/95 for 3 min EtOAc/heptane=5/95 to 30/70 over 15 min