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With potassium carbonate; In acetonitrile; at 25 - 100℃;
EXAMPLE A; Synthesis of {l-[5-(4,4,5,5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl] piperidin-3-yl} methanol:; Step 1 : Synthesis of [l-(5-bromopyrimidin-2-yl)piperidin-3-yl]methanol:; To a solution of 2-chloro-5-bromo-pyrimidine (2.0 g, 10.4 mmol) in acetonitrile (15 mL) were added piperidine-3yl-methanol (2.36 g, 20.8 mmol) and potassium carbonate (7.0 g, 52.0 mmol) at room temperature (-25 0C). The reaction mixture was heated at about 1000C for about 6 hours. It was cooled to room temperature (-25 0C) and concentrated under reduced pressure. The residue obtained was diluted with water and extracted with ethyl acetate (2x10OmL). The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford title compound (2.3 g).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 25 - 90℃;Inert atmosphere;
Step 2: Synthesis of {l-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2- yl]piperidin-3-yl}methanol :; To a solution of [l-(5-bromopyrimidin-2-yl)piperidin-3-yl]methanol (0.5 g, 1.83 mmol) in 1,4 dioxane (25 mL) were added bispinacolatodiborane (0.46 g, 3.3 mmol), potassium acetate ( 0.53 g, 5.4 mmol) and Pd (dppf)Cl2 (0.14 g, 0.18 mmol) under argon at room temperature (~25 0C). The mixture was heated at 80-90 0C for about 6 hours. It was cooled to room temperature (-25 0C), concentrated under reduced pressure and then purified through filtering column using sintered funnel full of 230-400 mesh size silica gel. It was eluted with 50% ethyl acetate in hexane and concentrated to afford title compound (0.4 g). MS m/e 289.93 (MH+).
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 2.0h;Schlenk technique; Inert atmosphere;
General procedure: To an oven dried 15 ml Schlenck tube, under N2, was added piperidin-3- ylmethanol (232 mg, 2.0 14 mmol), 2-chloroisonicotinonitrile (169 mg, 1.220 mmol), potassium carbonate (173 mg, 1.252 mmol) and DMSO (2 ml). The tube was cappedwith a rubber septum and was evacuated and backfilled with nitrogen four times. The mixture was heated at 80C (bath temp.) for 2 hours; the reaction progression being monitored by HPLC. The reaction mixture was diluted with ethyl acetate (60m1), washed with water (3Oml), brine (30m1) and dried (MgSO4). The residue was purified on ISCO using a 24 g Innoflash column (hexanes/EtOAc) to give the title material (222 mg,84%).
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