Hexachloroethane → 6-Chloronicotine

Temperature

0 °C

A 100 mL RB flask was placed under an argon atmosphere and degassed with argon by vacuum. The solvents (hexanes (4 ml) and toluene 12 ml)) were added to the flask. N,N-dimethylethanolamine (1.07 g, 1.21 ml, 12.0 mmol) was added. The reaction mixture was cooled to 0° C. N-butyl lithium (8.66 ml of 2.5M in hexanes, 21.6 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was cooled to −20° C. (S)-3-(1-methylpyrrolidin-2-yl)pyridine (650 mg, 0.64 ml, 4.01 mmol) was added. The reaction mixture was stirred −20° C. for 1 h. The reaction mixture was cooled to −78° C. and hexachloroethane (3.8 g, 16.0 mmol) was added in toluene (8 ml). The reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched cold with satd. NaHCO3 (4 mL). LCMS showed that the reaction gave the desired regioisomer in a 6:1 ratio over the undesired 6-chloro pyridine product. The reaction mixture was poured into 50 mL H2O and extracted with DCM (3×125 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 55% EtOAc in hexanes) to afford the desired product (467 mg, 59%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.56-2.05 (m, 3H) 2.16-2.40 (m and overlapping s, 5H) 3.09 (t, J=8.31 Hz, 1H) 3.17-3.29 (m, 1H) 7.23-7.32 (m, 1H) 7.68 (dd, J=8.12, 2.45 Hz, 1H) 8.30 (d, J=2.27 Hz, 1H)

1. customdegassed with argon by vacuum
2. additionThe solvents (hexanes (4 ml) and toluene 12 ml)) were added to the flask
3. additionwas added
4. stirringThe reaction mixture was stirred −20° C. for 1 h
5. temperatureThe reaction mixture was cooled to −78° C.
6. stirringThe reaction mixture was stirred at −78° C. for 1 h
7. customThe reaction was quenched cold with satd

ORD record

ord-95ab3f6d38da4c13a10fdca921ff89f5

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08481540B2