Hexachloroethane → 6-Chloronicotine

HRID 337279Notes

Reaction equation

HRID 337279 reaction equation
CN(C)CCO.[CH3:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:7])=[CH:14][N:15]=1

Participants

5

Reactant 3

HCID 6214HexachloroethaneHCID 79022-(Dimethylamino)ethanolHCID 89594Nicotine

Product 1

HCID 106317716-Chloronicotine

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
0 °C

Procedure

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)

Workup

  1. customA 100 mL round-bottomed flask was placed under an argon atmosphere
  2. customdegassed with argon by vacuum
  3. additionThe solvents (hexanes (4 ml) and toluene 12 ml)) were added to the flask
  4. additionwas added
  5. stirringThe reaction mixture was stirred −20° C. for 1 h
  6. temperatureThe reaction mixture was cooled to −78° C.
  7. stirringThe reaction mixture was stirred at −78° C. for 1 h
  8. customThe reaction was quenched cold with satd

Sources & evidence

ORD record
ord-c0998dc30c004b3388b3562106ef8625
Source dataset
uspto-grants-2014_11
Patent number
US08889682B2

Reaction notes

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