Diisopropylamine → Methyl 1-Boc-4-(chloromethyl)piperidine-4-carboxylate

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Reaction Steps

To a solution of diisopropylamine (22.6 mL, 159 mmol) in anhydrous THF (140 mL) in an oven-dried round-bottomed flask was added n-BuLi (65.4 mL, 163 mmol, 2.50 M in hexanes) dropwise at 0° C. The solution was stirred for 45 minutes and 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (20 g, 80 mmol) in THF (60 mL) was added dropwise at 0° C. and the mixture was stirred at 0° C. for 1 hour. Chloroiodomethane (17.9 mL, 239 mmol) was added dropwise and the mixture was stirred for 1 h. The mixture was quenched with 250 mL of saturated aqueous NaHCO3 followed by extraction with ethyl acetate (3×250 mL). The combined organic layers were washed (brine, 250 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil that was purified by silica chromatography using a Combiflash ISCO purification system (Teledyne Isco Inc., Lincoln, Nebr.) system to give 1-tert-butyl 4-methyl 4-(chloromethyl)piperidine-1,4-dicarboxylate (12 g, 52%). 1H NMR (CDCl3) δ 1.43 (s, 9H), 2.10-2.17 (m, 4H), 2.97 (br s, 2H), 3.56 (s, 2H), 3.74 (s, 3H), 3.83 (br s, 2H).

Provenance & Evidence