1．前言

杂环的酚羟基的通常较易被卤代，其也是杂环一种常见的官能团的转换方式之一，卤代反应常见的有氯代、溴代反应。另外，在存在吸电子基的杂环上，不仅酚羟基容易被卤代，而且烷氧基（甲氧基，乙氧基等）也很容易被卤代。因此其也是合成的一种策略。经常有文献首先将杂环卤代物用甲氧基取代后，利用甲氧基推电子效应完成一系列转化后，再将甲氧基卤代回来。

2. 氯代

杂环的酚羟基的氯代一般用三氯氧磷1,2,3或三氯氧磷与五氯化磷混合4,5处理。使用五氯化磷的条件更强，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6.

2.1 杂环的酚羟基的用三氯氧磷氯代反应示例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 杂环的酚羟基用三氯氧磷与五氯化磷混合处理氯代反应示例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 杂环的酚醚甲氧基用三氯氧磷氯代反应示例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

杂环的酚羟基的溴代常见的方法有用三溴氧磷7,8或四丁基溴化胺9。杂环烷氧基的溴代也可用三溴氧磷处理10.

3.1 杂环的酚羟基用 POBr₃溴代反应示例一7

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 杂环的酚羟基用 POBr₃溴代反应示例二8

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 杂环的酚羟基用四丁基溴化胺法溴代反应示例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 杂环的甲氧基用PBr3溴代反应示例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%).

参考文献：

1. J. Med. Chem.;45; 13; 2002; 2841-2849.

2. J. Org. Chem.;68; 18; 2003; 6919-6927.

3. J. Med. Chem.;43; 22; 2000; 4288-4312.

4. J. Amer.Chem. Soc.; 70; 1948; 1494-1497.

5. J. Amer.Chem. Soc.; 70; 1948; 3712-3715.

6. J.Herterocyclic Chem.; 30; 6; 1993;1623-1628.

7. J. Org. Chem.;62; 9; 1997; 2774-2781.

8. J. Med. Chem.;47; 10; 2004; 2453-2465.

9. J. Org. Chem.;64; 26 1999; 9658-9667.

10. Chem. Pharm.Bull.; 38; 11; 1990; 2919-2925.

本文内容来源于网络，版权归原作者所有