1-Bromo-2-iodobenzene → (2-Bromophenyl)(1-(2-(trimethylsilyl)ethanesulfonyl)piperidin-3-yl)methanol

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Reaction Conditions

Reaction Steps

A three neck 200-mL flask was charged with anhydrous THF (150 mL) and 1-bromo-2-iodobenzene (5.81 g, 20.5 mmol, 1.5 equiv), and cooled to −40° C. Isopropyl magnesium bromide (1.0 M in THF, 19.9 mL, 19.9 mmol, 1.45 equiv) was added to the solution via syringe at a rate such that the internal temperature did not rise above −35° C. An aliquot was removed, quenched with water and analyzed by LC-MS. The observed amount of bromobenzene showed >90% conversion to the desired Grignard reagent. A solution of 1-(2-trimethylsilyl-(ethanesulfonyl))piperidine-3-carbaldehyde (3.8 g, 13.7 mmol) in 20 mL of THF was added to solution containing the Grignard reagent at such a rate that the internal temperature did not rise above −35° C. The mixture was stirred for 1 h at −40° C.; after this period LC-MS analysis of an aliquot showed consumption of the aldehyde and formation of two peaks with the desired mass, consistent with formation of two diastereomers. The mixture was quenched with methanol and the THF removed in vacuo. The resulting solid was partitioned between EtOAc and water, and filtered through a pad of Celite to remove a sticky white solid. The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated. The mixture of alcohols was purified by flash chromatography on 120 g silica, eluting with 0 to 50% EtOAc in hexanes. No attempt was made to separate the two diastereomers. This afforded (2-bromophenyl)(1-(2-(trimethylsilyl)ethanesulfonyl)piperidin-3-yl)methanol (3.64 g, 61%) as a white foam. 1H NMR (CDCl3) δ 0.01 (s, 9H), 0.95-2.06 (m, 8H), 2.6-3.0 (m, 6H), 3.6-3.9 (m, 3H), 4.96 (bs, 1H), 7.13 (m, 1H), 7.29 (m, 1H), 7.44 (m, 2H).

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