Hexachloroethane → 6-Chloronicotine

Participants

Reaction Conditions

Reaction Steps

A 100 mL round-bottomed 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 CH2Cl2 (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, 3 H) 2.16-2.40 (m and overlapping s, 5 H) 3.09 (t, J=8.31 Hz, 1 H) 3.17-3.29 (m, 1 H) 7.23-7.32 (m, 1 H) 7.68 (dd, J=8.12, 2.45 Hz, 1 H) 8.30 (d, J=2.27 Hz, 1 H)

Provenance & Evidence