Reaktion #220641

Reaktionsgleichung

2-bromomethyl-5-chloropyridine

3-bromophenyl acetone

cesium hydroxide monohydrate

→

title compound

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

Lösungsmittel

CH2Cl2

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigewas used immediately for the ensuing reaction
2. 2
   Temperaturto slowly warm to room temperate overnight
3. 3
   SonstigeThe reaction mixture was partitioned between EtOAc (100 mL) and water (100 mL)
4. 4
   SonstigeThe organic layer was separated
5. 5
   Extraktionthe aqueous layer extracted with EtOAc (2×100 mL)
6. 6
   TrocknenThe combined organic extracts were dried over anhydrous sodium sulfate
7. 7
   Filtrationfiltered
8. 8
   Einengenconcentrated to dryness
9. 9
   Sonstigethe residue was purified by flash column chromatography on silica gel
10. 10
    Wascheneluted with 5 to 40% EtOAc in hexane

Vorschrift

A suspension of 5-chloro-2-methylpyridine (Reference Example 18, 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).

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