Ammonium Chloride → 4-Chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol

HRID 46385Notes

Reaction equation

HRID 46385 reaction equation
Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15]C)[CH:5]=[CH:4][N:3]=1.Cl.[NH:18]1[CH2:21]C[CH2:19]1.C(N(CC)C(C)C)(C)C.CN(C)C(=O)C.[Cl-].[NH4+]>O>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([OH:15])=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:18]([CH3:21])[CH3:19])[CH:7]=2)[CH:13]=1

Participants

7

Reactant 5

HCID 25517Ammonium ChlorideHCID 31374DimethylacetamideHCID 81531DiisopropylethylamineHCID 12308726Azetidine hydrochlorideHCID 594364732-Chloro-4-(5-chloro-2-methoxyphenyl)pyridine

Product 1

HCID 1360636144-Chloro-2-[2-(dimethylamino)pyridin-4-yl]phenolYield 33%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
170 °C

Procedure

A mixture of 2-chloro-4-(5-chloro-2-methoxyphenyl)pyridine (Preparation 866, 157 mg, 0.618 mmol), azetidine hydrochloride (120 mg, 1.2 mmol), and N,N-diisopropylethylamine (220 uL, 1.2 mmol) in N,N-dimethylacetamide (4.1 mL, 44 mmol) was heated 20 minutes at 170° C. under microwave irradiation. The reaction mixture was poured into water and saturated aqueous ammonium chloride and extracted with ethyl acetate (3×). The combined organic layers were washed with water then brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash chromatography (12 g SiO2, hexanes to 9:1 ethyl acetate-methanol). A single peak containing the major products eluted from the column. The appropriate fractions were concentrated in vacuo. The residue was dissolved in 1 mL of dimethylsulfoxide, filtered through a plug of cotton, and purified by reverse-phase HPLC to afford 4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol as a tan solid (50 mg, 33%) followed by 4-chloro-2-(2-chloropyridin-4-yl)phenol as a light pink solid (24 mg, 16%). Unexpectedly 4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol was isolated as the main product and none of the intended product was isolated. This presumably occurred due to decomposition of the dimethylacetamide to provide dimethylamine which reacted preferentially to give 4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol

Workup

  1. extractionextracted with ethyl acetate (3×)
  2. washThe combined organic layers were washed with water
  3. dry with materialbrine, dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. concentrationconcentrated onto diatomaceous earth
  7. custompurified by automated flash chromatography (12 g SiO2, hexanes to 9:1 ethyl acetate-methanol)
  8. additionA single peak containing the major products
  9. washeluted from the column
  10. concentrationThe appropriate fractions were concentrated in vacuo
  11. dissolutionThe residue was dissolved in 1 mL of dimethylsulfoxide
  12. filtrationfiltered through a plug of cotton
  13. custompurified by reverse-phase HPLC

Sources & evidence

ORD record
ord-4c702b3ce1774084bd35b846faefa164
Source dataset
uspto-grants-2013_09
Patent number
US08541588B2

Reaction notes

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