Dimethylformamide → 2-Bromo-6-(chloromethyl)pyridine

HRID 1446078Notes

Reaction equation

HRID 1446078 reaction equation
[Li+].[CH3:2]CC[CH2-].[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9]N=1.CN(C=O)C.[NH4+:19].[Cl-:20].O=S(Cl)Cl>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.CO>[Br:6][C:7]1[N:19]=[C:9]([CH2:2][Cl:20])[CH:10]=[CH:11][CH:12]=1

Participants

9

Reactant 5

HCID 6228DimethylformamideHCID 24386Thionyl ChlorideHCID 25517Ammonium ChlorideHCID 61028n-Butyl lithiumHCID 693532,5-Dibromopyridine

Product 1

HCID 216984342-Bromo-6-(chloromethyl)pyridineYield 83%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 1140TolueneSolventHCID 6212ChloroformSolvent

Conditions

Temperature
-78 °C

Procedure

N-Butyllithium (10 mL, 25.32 mmol, 2.5 M solution in hexanes) was added dropwise over a period of 20 min at −78° C. to a degassed solution of 2,5-dibromopyridine (5.0 g, 21.1 mmol) in toluene (250 mL), and the solution was then stirred for 2 h at −78° C. DMF (2.1 mL, 27.43 mmol) was then added dropwise, and the reaction was left at −78° C. for 1 h. MeOH (20 mL) and NaBH (1.60 g, 42.2 mmol) were then added at −78° C., and the reaction mixture was allowed to slowly reach room temperature and stirring was continued for 16 h. Saturated aqueous NH4Cl (100 mL) was added at −10° C. and stirring was continued for 30 min. The two layers were separated. The toluene layer was concentrated and dried in vacuo to give 6-bromo-2-pyridinyl)methanol (3.74 g, 94%) as a light yellow oil. A solution of this oil (3.74 g, 19.8 mmol) in CHCl3 (250 mL) was treated with SOCl2 (25 mL) at 0° C., then the reaction mixture was refluxed for 1 h, poured into ice-water, and extracted into iPr2O. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to dryness, to give the title compound as a yellow oil (3.42 g, 83%). APCI MS m/z 205.9, 207.9 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.59 (t, J=7.7 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 4.63 (s, 2H).

Workup

  1. waitthe reaction was left at −78° C. for 1 h
  2. customwas allowed to slowly reach room temperature
  3. stirringstirring
  4. waitwas continued for 16 h
  5. stirringstirring
  6. waitwas continued for 30 min
  7. customThe two layers were separated
  8. concentrationThe toluene layer was concentrated
  9. customdried in vacuo
  10. customto give 6-bromo-2-pyridinyl)methanol (3.74 g, 94%) as a light yellow oil
  11. temperaturethe reaction mixture was refluxed for 1 h
  12. extractionextracted into iPr2O
  13. washThe combined organic layers were washed with brine
  14. dry with materialdried (MgSO4)
  15. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-3fcbc5c272d84dfa85d778fdcd9d1286
Source dataset
uspto-grants-2010_02
Patent number
US07666864B2

Reaction notes

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