3-Iodobenzyl bromide → 1'-(1-(3-Iodobenzyl)-4-hydroxypiperidin-3-yl)-3,4-dihydrospiro[naphthalene-1(2H),4'-piperidine]

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Reaction Steps

A mixture of 21c and 22c derived from a mixture of 19c and 20c as described above (676 mg, 1.81 mmol), 3-iodobenzylbromide (2.17 mmol, 645 mg), and triethylamine (10 mL) in absolute EtOH (20 mL) was refluxed for 18 h. Volatiles were removed under reduced pressure and the red residue was treated with water. After extraction in dichloromethane (3×30 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a dark red semi-solid residue. Chromatographic purification (silica gel, 50% ethyl acetate-hexanes) afforded 276 mg (30%) of the crude product as a yellow oil. The two regioisomers were separated by HPLC (Silica gel, Hexane/Isopropanol/Triethylamine: 98/2/0.02) and 13d was obtained as a white crystalline solid (166 mg, 18%). Only a trace of the other isomer was recovered. The hydrochloride of 13d was prepared in satd methanolic saturated HCl and subsequently recrystallized from 50% i-PrOH-hexanes to provide a white powder; mp 245° C. 1H NMR (CDCl3)δ1.59-2.06 (m, 8, 2 N-CH2 --CH2), 2.41-2.48 (m, 2, Ar-CH2 --CH 2), 2.52-2.62 (m, 2, CH2CHOH), 2.75-2.78 (m, 4, Ar-CH2 --CH2 --CH2), 2.83-2.92 (m, 2, CH2 --CH2 --CHOH), 3.01-3.06 (d, 2, N-CH2 --CHN, J=10.0 Hz), 3.38-3.56(m, 3, Ar-CH2 --N+CH-N), 3.85 (s, 1, CH--OH), 7.02-7.31 (m, 5, arom.), 7.44-7.48(d, 1, arom., J=7.8 Hz), 7.58-7.62 (d, 1, arom., J=7.9 Hz), 7.68 (s, 1, arom.).

Provenance & Evidence