1-(3-Bromophenyl)propan-2-one → 3-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone

HRID 30379Notes

Reaction equation

HRID 30379 reaction equation
Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=1.O.[OH-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=2)[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=1

Participants

6

Reactant 3

HCID 27340931-(3-Bromophenyl)propan-2-oneHCID 222705252-(Bromomethyl)-5-chloropyridineHCID 23679066Caesium hydroxide--water (1/1/1)

Product 1

HCID 222705133-(3-Bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6344DichloromethaneSolvent

Procedure

A suspension of 5-chloro-2-methylpyridine (Reference Example 52, Step A, 6.4 g, 50 mmol) and N-bromosuccinimide (12.5 g, 70 mmol) in 100 mL carbon tetrachloride was heated to gentle reflux (bath temperature 90° C.), and 2,2′-azobisisobutyronitrile (0.74 g) was added in several portions over 30 min. After stirring at this temperature for 5 h, the reaction mixture was concentrated. The resulting slurry was diluted with EtOAc (100 mL) and was washed with water (100 mL), saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate, and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 2 to 15% ether in CH2Cl2/hexane (1:1) to afford 2-bromomethyl-5-chloropyridine (6.0 g, 60%), which was used immediately for the ensuing reaction. Thus, to a vigorously stirred solution of 2-bromomethyl-5-chloropyridine (6.0 g, 29 mmol) and 3-bromophenyl acetone (Step A, 6.0 g, 28 mmol) and tetrabutylammonium iodide (20 mg) in 30 mL CH2Cl2 at −78° C. was added cesium hydroxide monohydrate (10 g, 60 mmol), and the reaction was allowed to slowly warm to room temperate overnight. The reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5 to 40% EtOAc in hexane to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 8.44 (d, 1H), 7.66 (dd, 1H), 7.46-7.41 (m, 2H), 7.24 (t, 1H), 7.22 (d, 1H), 7.15 (d, 1h), 4.42 (dd, 1H), 3.54 (dd, 1H), 3.07 (dd, 1H), 2.12 (s, 3H). LC-MS: m/e 338 (M+H)+ (3.0 min).

Workup

  1. customwas used immediately for the ensuing reaction
  2. temperatureto slowly warm to room temperate overnight
  3. customThe reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL)
  4. customThe organic layer was separated
  5. extractionthe aqueous layer extracted with EtOAc (2×100 mL)
  6. dry with materialThe combined organic extracts were dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated to dryness
  9. customthe residue was purified by flash column chromatography on silica gel
  10. washeluted with 5 to 40% EtOAc in hexane

Sources & evidence

ORD record
ord-d7c3459508d44415a4e250e9bdc6c9b9
Source dataset
uspto-grants-2008_09
Patent number
US07423067B2

Reaction notes

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