1．前言
雜環(huán)的酚羥基的通常較易被鹵代，其也是雜環(huán)一種常見的官能團的轉(zhuǎn)換方式之一，鹵代反應(yīng)常見的有氯代、溴代反應(yīng)。另外，在存在吸電子基的雜環(huán)上，不僅酚羥基容易被鹵代，而且烷氧基（甲氧基，乙氧基等）也很容易被鹵代。因此其也是合成的一種策略。經(jīng)常有文獻首先將雜環(huán)鹵代物用甲氧基取代后，利用甲氧基推電子效應(yīng)完成一系列轉(zhuǎn)化后，再將甲氧基鹵代回來。
2. 氯代
雜環(huán)的酚羥基的氯代一般用三氯氧磷1,2,3或三氯氧磷與五氯化磷混合4,5處理。使用五氯化磷的條件更強，用于難以發(fā)生的雜環(huán)的酚羥基的氯代反應(yīng)。雜環(huán)烷氧基的氯代也可用三氯氧磷直接處理6.
2.1 雜環(huán)的酚羥基的用三氯氧磷氯代反應(yīng)示例1
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 crystals 2 (60 g,0.21mol, 78% yield).
2.2 雜環(huán)的酚羥基用三氯氧磷與五氯化磷混合處理氯代反應(yīng)示例5
To a solution of 10.5 g of 1 in 16 mL ofphosphorus oxychloride was heated to reflux and added 20 g of phosphoruspentachloride 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%).
2.3 雜環(huán)的酚醚甲氧基用三氯氧磷氯代反應(yīng)示例6
A mixture of 1 (10 mmol) and phosphorylchloride (20 mL) was refluxed for 0.5 hr. Then the excess of phosphoryl chloride was evaporated invacuo. The residue was carefullypoured onto ice (30 g) 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.
3．溴代
雜環(huán)的酚羥基的溴代常見的方法有用三溴氧磷7,8或四丁基溴化胺9。雜環(huán)烷氧基的溴代也可用三溴氧磷處理10.
3.1 雜環(huán)的酚羥基用 POBr3溴代反應(yīng)示例一7
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.
3.2 雜環(huán)的酚羥基用 POBr3溴代反應(yīng)示例二8
Phosphorus oxybromide (25.0 g, 87.2 mmol) was added totoluene (55 mL) at room temperature. Next, 1 (21.1 g, 79.3 mmol)and quinoline (9.5 mL) were added consecutively to mechanically stirred reactionmixture to 90-100 degree. The vigorousreaction was monitored by TLC (ethyl acetate/hexane 5:15). After reaction completion, the toluene layer was separated. The remaining brownish solid was extractedwith boiling toluene (3 x 260 mL). Thecombined toluene solutions were washed with 5% aqueous NaHCO3, driedover anhydrous sodium sulfate, and concentrated by rotary evaporation. Flash column chromatography (95:5hexane/ethyl acetate) workup gave 2 (21.1g, 81.1%) as a yellow solid.
3.3 雜環(huán)的酚羥基用四丁基溴化胺法溴代反應(yīng)示例9
1 (177 g, 1.01 mol),phosporus pentoxide (300 g, 1.06 mol) and tetrabutyl ammonium bromide (391 g,1.21 mol) was mixed in toluene (2 L) and heated to reflux for 4 h. The mixture was cooled to room temperatureand water (1 L) was added carefully with stirring and cooling. The mixture was stirred for 2 h and thenfiltered 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 2 as a clear yellowoil.
3.4 雜環(huán)的甲氧基用PBr3溴代反應(yīng)示例10
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%).
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