反应详情

温度

130 °C

A 500-mL RB-flask was charged with solid 3,5-dibromo-2,6-dimethylpyridin-4-ol, hydrobromide (94 g, 260 mmol) and POCl3 (150 ml, 1609 mmol) was added. To this white slurry was added N,N-dimethylaniline (39.5 ml, 312 mmol) and the reaction mixture was heated to 130° C. (oil bath temp). After stirring for 2 h, the reaction mixture was cooled, concentrated and the brown residue taken up in toluene (100 mL) and concentrated to remove any unreacted POCl3. Then, the residue was treated with ice (250 g) for 30 min and carefully neutralized with powder Na2CO3, extracted with CH2Cl2 (3×250 mL). The combined organic layers dried (MgSO4/C), filtered, concentrated to give slurry which was dissolved in ether (500 mL), filtered through a plug of silica gel. The silica gel pad was washed with 1:1 Ether/Hex (1.5-lit). The filtrate was concentrated to give white slurry which was triturated with hexanes (200 mL) and left in the freezer (−10° C., 2 h). The liquid was decanted and solids were rinsed with cold hexanes (4×50 mL) and dried overnight under high vacuum (required to remove dimethylaniline) to afford 3,5-dibromo-4-chloro-2,6-dimethylpyridine (49.2 g, 164 mmol, 63.3% yield) as pale greenish-yellow solid. The decanted solvent was concentrated and purified by flash chromatography using 1-lit each hexanes, 0.5, 1, 2 and 5% EtOAc/Hex to afford additional 3,5-dibromo-4-chloro-2,6-dimethylpyridine (18.763 g, 62.7 mmol, 24.13% yield) as greenish-yellow solid. 1H NMR (500 MHz, CDCl3) δ 2.59 (s, 6H). LCMS (M+H)=300.0.

1. additionwas added
2. temperaturethe reaction mixture was cooled
3. concentrationconcentrated
4. concentrationconcentrated
5. customto remove any unreacted POCl3
6. additionThen, the residue was treated with ice (250 g) for 30 min
7. extractionextracted with CH2Cl2 (3×250 mL)
8. dry with materialThe combined organic layers dried (MgSO4/C)
9. filtrationfiltered
10. concentrationconcentrated
11. customto give slurry which
12. filtrationfiltered through a plug of silica gel
13. washThe silica gel pad was washed with 1:1 Ether/Hex (1.5-lit)
14. concentrationThe filtrate was concentrated
15. customto give white slurry which
16. customwas triturated with hexanes (200 mL)
17. waitleft in the freezer (−10° C., 2 h)
18. customThe liquid was decanted
19. washsolids were rinsed with cold hexanes (4×50 mL)
20. dry with materialdried overnight under high vacuum (required to remove dimethylaniline)