Carbon Dioxide → 1-[4-benzyloxymethyl-3-(1-methylpyrrolidin-2-yl)-4H-pyridin-1-yl]-2,2-dimethyl-propan-1-one

Temperature

-78 °C

To a stirred solution of (benzyloxymethyl)tributyl stannane (prepared according to reference 1) (0.308 g, 0.75 mmol) in THF (0.75 mL) cooled at −78° C. was added n-butyllithium (0.35 mL, 0.75 mmol). After stirring at −78° C. for 30 min, the Lipshultz reagent (3 mL, 0.75 mmol) was introduced dropwise, and the mixture was allowed to stir for 30 min at −78° C. In a separate flask, a stirred solution of nicotine (0.08 mL, 0.5 mmol) in THF (1 mL) was cooled at 0° C. and treated with pivaloyl chloride (0.06 mL, 0.5 mmol). This solution was then stirred at 0° C. for 1.5 h. The cuprate solution prepared above was then transferred via a double tipped needle surrounded by a layer of dry ice to the pyridinium salt of nicotine previously cooled to −78° C. After addition of a saturated aqueous solution of NH4Cl (10 mL), the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with 20% NH4Cl/NH4OH, water and brine, and were dried over K2CO3. After evaporation of the solvent under reduced pressure, the crude material was purified by radial PLC (hexanes) to afford 0.107 g (70%) of 1-[4-benzyloxymethyl-3-(1-methylpyrrolidin-2-yl)-4H-pyridin-1-yl]-2,2-dimethyl-propan-1-one as a yellow oil. IR (thin film, neat, NaCl) 2928, 1772, 1724, 1656, 1599, 1454, 1364, 1267, 1153, 1100 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.01±6.94 (m, 5H), 6.80 (d, 1H, J=8 Hz), 4.93 (dd, 1H, J=4.8 Hz and 8 Hz), 4.18 (d, 2H, J=6.8 Hz), 3.37 (dd, 1H, J=4 Hz and 8.4 Hz), 3.05 (t, 1H, J=8 Hz), 2.87-2.83 (m, 1H), 2.74 (t, 1H, J=7.6 Hz), 2.25 (t, 1H, J=7.6 Hz), 1.85 (s, 3H), 1.81-1.77 (m, 1H), 1.58-1.37 (m, 4H), 1.01 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 173.65, 138.51, 128.09, 127.28, 127.22, 124.40, 123.45, 119.32, 109.80, 74.32, 72.78, 70.55, 56.69, 40.32, 39.31, 35.62, 30.74, 28.06, 22.74; HRMS Calcd for C23H32N2O2: 369.2542 [M+H]+. Found: 369.2543 [M+H]+. [α]D28+26.6 (c 5.6, CH2Cl2). Reference 1: Kaufman, T. S. Synlett, 1997, 1377.

1. stirringto stir for 30 min at −78° C
2. stirringThis solution was then stirred at 0° C. for 1.5 h
3. temperaturepreviously cooled to −78° C
4. extractionthe aqueous layer was extracted with EtOAc (3×)
5. washThe combined organic layers were washed with 20% NH4Cl/NH4OH, water and brine
6. dry with materialwere dried over K2CO3
7. customAfter evaporation of the solvent under reduced pressure
8. customthe crude material was purified by radial PLC (hexanes)

ORD record

ord-77445dfef7864f7bad6018f5c4ee3ca8

Source dataset

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07875724B2