一、氯代
杂环neutralized的酚羟基的氯代一般用三氯氧磷【J. Med. Chem.;45; 13; 2002; 2841-2849.neutralized；J. Org. Chem.;68; 18; 2003; 6919-6927neutralized；J. Med. Chem.;43; 22; 2000; 4288-4312.】或三氯氧磷与五氯化磷混合处理。使用五氯化磷的条件更强neutralized，用于难以发生的杂环的酚羟基的氯代反应。杂环烷氧基的氯代也可用三氯氧磷直接处理.
2-Hydroxy-3-iodo-5-nitropyridine 1(70.5 g, 0.27 mol) was added to quinoline (16 mL, 0.133mol). The reaction flask was cooled to 5degree and phosphoryl chloride (25 mL, 0.27 mol) was addeddropwise. The mixture was blanketed withargon and heated to 120 degree for 2 h. Upon complete consumption of the precursor, as indicated by TLC, themixture was cooled to room temperature and 100 mL of H2O wasadded. The mixture was then cooled to 0degree, and the resulting brown solid was filtered. Recrystallization from ethanol gavesand-color crystals2 (60 g,0.21mol, 78% yield).
【J. Med. Chem.;45; 13; 2002】
To a solution of 10.5 g of 1in 16 mL of phosphorus oxychloride was heated to reflux and added 20 g ofphosphorus pentachloride in small portions over a period of 1.5 hr. The oil bath temperature was then raised to165 degree and kept there for 1 hr. Thephosphorus oxychloride was removed under reduced pressure, 50 g of ice thenadded, and the mixture made strongly basic by adding a concentrated KOHsolution. When this was steam distilled,a colorless heavy oil was obtained, which was separated by two extractions with100-mL portions of ether. The ether wasdried and removed, and the residue distilled, giving a colorless oil (4.0 g,34%).
【J. Amer.Chem. Soc.; 70; 1948; 3712-3715】
A mixture of 1(10 mmol) and phosphorylchloride (20 mL) was refluxed for 0.5 hr. Then the excess of phosphorylchloride was evaporated in vacuo. The residue was carefully poured onto ice (30g) and neutralized with conc. ammonia at 0-5 degree. The solid was filtered off, washed with waterand air-dried. The product was purifiedby crystallized from ethanol to give 86-94% yields.
【J.Herterocyclic Chem.; 30; 6; 1993;1623-1628】
二、溴代
杂环的酚羟基的溴代常见的方法有用三溴氧磷或四丁基溴化胺。杂环烷氧基的溴代也可用三溴氧磷处理.
A stirred mixture of 1(0.8 g, 4.25 mmol) and freshly prepared POBr3 (8.0 g,28 mmol) in anisole (8.0 mL) was heated at 145 degree for 2 days. After cooling, the reaction mixture waspoured into ice water (300 mL) and basified with saturated sodium carbonatesolution until the PH was 8-9. Themixture was extracted with CH2Cl2 (3 x 300 mL); thecombined extracts were dried over anhydrous sodium sulfate and evaporated in vacuo. Purification of the residue by flash chromatography (silica gel, 1:1 CH2Cl2:Et2O) and recrystallization from ethanol gave bromide 2 (0.831 g, 60%) as colorless, fineneedles.
【J. Org. Chem.;62; 9; 1997; 2774-2781】
Phosphorus oxybromide(25.0 g, 87.2 mmol) was added to toluene (55 mL) at room temperature. Next, 1(21.1 g, 79.3 mmol) and quinoline (9.5 mL) were added consecutively tomechanically stirred reaction mixture to 90-100 degree. The vigorous reaction was monitored by TLC(ethyl acetate/hexane 5:15). After reaction completion, the toluene layerwas separated. The remaining brownishsolid was extracted with boiling toluene (3 x 260 mL). The combined toluene solutions were washedwith 5% aqueous NaHCO3, dried over anhydrous sodium sulfate, and concentratedby rotary evaporation. Flash columnchromatography (95:5 hexane/ethyl acetate) workup gave2 (21.1 g, 81.1%) as a yellow solid.
【J. Med. Chem.;47; 10; 2004; 2453-2465】
1(177 g, 1.01 mol), phosporus pentoxide (300 g, 1.06 mol) and tetrabutylammonium bromide (391 g, 1.21 mol) was mixed in toluene (2 L) and heated toreflux for 4 h. The mixture was cooledto room temperature and water (1 L) was added carefully with stirring andcooling. The mixture was stirred for 2 hand then filtered through a pad of Celite, and the layers were separated. The toluene layer was washed with brine andconcentrated in vacuo. The product was passed through a pad ofsilica gel (50 g) and eluted with ethyl acetate:hexane (10:1) to give 202 g(84% yield) of 2as a clear yellowoil.
【J. Org. Chem.;64; 26 1999; 9658-9667】
Phosphorustribromide (3 mL) was added to a solution of 1(1.3 g) in DMF (30 mL) inan ice bath. The reaction was furtherstirred for 2 hr at 80 degree and then poured into ice-water. The aqueous mixture was made alkaline withNaOH and extracted with CH2Cl2. The extract was washed with brine, dried andevaporated. The residue waschromatographed on silica gel using CH2Cl2–acetone (50:1)as an eluent to give product 2(1.04 g, 65%).
【Chem. Pharm.Bull.; 38; 11; 1990; 2919-2925.】
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