AppelReactionandMitsunobuReaction.docx

1、AppelReactionandMitsunobuReactionAppel Reaction and Mitsunobu ReactionAppel 反应Appel反应，用三苯基膦和四氯化碳将醇转化为氯代烃。此反应是用于引入卤原子的一种较为温和的方法。伯醇、仲醇和多数叔醇都能顺利发生反应。用四溴化碳或溴作为卤原子源，或者用碘甲烷或碘，可得到相应的溴代烃和碘代烃。首先三苯基膦与四氯化碳生成鏻正离子和三氯甲基负离子离子对，三氯甲基负离子从醇夺取质子，生成氯仿，同时醇转化为烷氧负离子。烷氧负离子对鏻正离子进行亲核取代，得到含 P-O 键的中间体 (5)和氯离子，然后氯离子对 (5)进行亲核进攻，产

2、生三苯基氧膦和产物氯代烃 (6)。如果以叔醇为底物，则最后一步生成氯代烃和三苯基氧膦为 SN1 机理。反应的推动力是固体三苯基氧膦的生成，它从反应混合物中分离出来。其中含有键能较强的 P=O 双键，利于反应进行。可以这样认为，四氯化碳中的一个氯在反应后转移到氯代烃中，自身接受醇的羟基氢，生成氯仿。醇的羟基氧则被三苯基膦接受，三苯基膦变为三苯基氧膦。醇和有机磷氯化物的反应三苯基膦氯化物，如Ph3PX2, PH3P+CX3X- 以及亚磷酸三苯酯氯化物如(PhO)3PX2、(PhO)3P+RX-，在和醇进行氯置换反应，具有活性大，反应条件温和等特点。由于反应中产生的氯化氢很少，因此不容易发生氯化氢引

3、起的副反应。三苯基膦和六氯代丙酮（HCA）复合物和Ph3P/CCl4相似，也能将光学活性的烯丙醇在温和条件下转化成为构型翻转的烯丙氯代物，而且不发生异构、重排等副反应。这个试剂比Ph3P/CCl4更温和，反应迅速，特别适宜于用其他方法易引起重排的烯丙醇。此外，三苯膦或亚磷酸酯和N-氯代酰胺组成的复合氯化剂与上述试剂相似，但特别适宜于对酸不稳定的醇或者是甾体醇的氯置换反应，也可用于缺电子的体系的羟基氯置换。Example A: A dry, 300-ml., three-necked flask is equipped with a magnetic stirring bar and reflu

4、x condenser (to which is attached a Drierite-filled drying tube) and charged with 90 ml. of carbon tetrachloride and 15.42 g. of geraniol (0.1001 mole). To this solution is added 34.09 g. (0.1301 mole) of triphenylphosphine, and the stirred reaction mixture is heated under reflux for 1 hour. This mi

5、xture is allowed to cool to room temperature; dry pentane is added (100 ml.), and stirring is continued for an additional 5 minutes.The triphenylphosphine oxide precipitate is filtered and washed with 50 ml. of pentane. The solvent is removed from the combined filtrate with a rotary evaporator under

6、 water aspirator pressure at room temperature. Distillation of the residue through a 2-cm. Vigreux column attached to a short-path distillation apparatus provides 13.014.0 g. (7581%) of geranyl chloride, b.p. 4749 (0.4 mm.), n23D = 1.4794.Example B: To a cooled 25 ml round-bottom flask containing 1

7、(50 mg, 0.16 mmol) and Ph3P (51 mg, 0.2 mmol) was added hexachloroacetone (HCA, 0.05 ml, 0.3 mmol) in 1 ml of CH2Cl2. The reaction mixture was allowed to come to room temperature and stirred overnight. The mixture was subjected to purification by flash silica gel column chromatography, with elution

8、first by hexane to remove the HCA and then by 5% ethyl acetate/hexanes to give 49 mg (93%) of 2.醇和有机磷溴化物的反应三苯膦溴化物，如Ph3PX2, PH3P+CX3X- 以及亚磷酸三苯酯溴化物如(PhO)3PX2、(PhO)3P+RX-，在和醇进行溴置换反应是，具有活性大，反应条件温和等特点。由于反应中产生的溴化氢很少，因此不容易发生溴化氢引起的副反应。这两类试剂均可由三苯膦或亚磷酸三苯酯和溴素或溴代烷直接制得，不经过分离纯化即可和醇进行反应。其反应历程是这些试剂和醇反应生成醇烷氧基取代的三苯膦加

9、成物或相应的亚磷酸酯，后经溴素负离子的SN2反应，生成溴化物，同时发生构型翻转。这些试剂的应用很广泛，常以DMF或HMPTA作为溶剂进行溴置换反应，也可在较温和的条件下将光学活性的仲醇转化成构型翻转的溴代烃，或对某些在酸性条件下不稳定的化合物进行溴化。此外，三苯膦或亚磷酸酯和N-溴代酰胺组成的复合溴化剂与上述试剂相似，但特别适宜于对酸不稳定的醇或者是甾体醇的溴置换反应，也可用于缺电子的体系的羟基溴置换。Example A： To a solution of 1 (4 g, 22.5 mmol) in CH2Cl2 (50 ml) at room temperature was added CB

10、r4 (11.2 g, 34 mmol) followed by triphenylphosphine (8.8 g, 33 mmol). The reaction mixture was allowed to stir for 2.5 h, and the solvent was removed under vacuum. Chromatography (30% EtOAc-hexanes) afforded 5.91 g (98%) of product 2 as an off-white solid.Example B ： The alcohol (5.34 g, 16.7 mmol)

11、and CBr4 (16.6 g, 50 mmol) were dissolved in 100 ml of dichloromethane. This solution was treated with solid triphenylphosphine (13.1 g, 50 mmol) over a 10 min period. This solution was allowed to stir for 18 h, and then 10 ml of ethanol was added. After 2 h this solution was treated with 100 ml of

12、Et2O by dropwise addition over a 0.5 h period. The mixture was filtered, and the filtrate and washings were trhen concentrated and purified by flash chromatography to give 4.79 g (74% yield) of the title compound. This material recrystallized (Et2O/hexane) on standing to give mp 87-88Example C：In a

13、well-ventilated hood, a 2-L, three-necked, round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel, and a reflux condenser, is charged under nitrogen with 327 g (1.24 mol) of triphenylphosphine, and 1.24 L of anhydrous dichloromethane . The solution is vigorously stirred

14、 under acetone-dry ice cooling, as 199 g (64.1 ml, 1.25 mol) of bromine is added over a period of 0.5 hr at 30C to 15C under nitrogen. After an additional 15 min of stirring, a mixture of 116 g (1.18 mol) of 1-cyclopropylcyclopropanol and 93.5 g (95.6 ml, 1.18 mol) of anhydrous pyridine is added dro

15、pwise at 15C over a period of 2 hours. The mixture is stirred at 20C for an additional 24 hours under nitrogen. The reflux condenser and the dropping funnel are removed. The flask is immersed in an oil bath and connected to a 2-L, two-necked, round-bottomed flask via a 90 angle glass tube. The secon

16、d flask is cooled with acetone-dry ice. All the volatile material is bulb-to-bulb distilled, at first under water-aspirator vacuum and 30C oil bath temperature, and then under further reduced pressure (0.1 mm) with a 100C oil bath. The distillation is continued until the temperature in the first fla

17、sk reaches 80C. The receiver flask is allowed to warm to 20C, and the solvent is removed by distillation at atmospheric pressure using a 30-cm Vigreux column. The residue is distilled under reduced pressure to give 117.1 g (62%) of 1-bromo-1-cyclopropylcyclopropane.醇和有机磷碘化物的反应(PhO)3P, CH3I体系EXAMPLE

18、1:A 500-ml., two-necked, round-bottomed flask fitted with a reflux condenser equipped with a calcium chloride drying tube is charged with 136 g. (115 ml., 0.439 mole) of triphenyl phosphite, 35.2 g. (0.400 mole) of neopentyl alcohol, and 85 g. (37 ml., 0.60 mole) of methyl iodide. A thermometer of s

19、ufficient length extends into the liquid contents of the flask. The mixture is heated under gentle reflux with an electric heating mantle until the temperature of the refluxing liquid rises from its initial value of 7580 to about 130, and the mixture darkens and begins to fume. The time required is

20、about 24 hours. It is necessary to adjust the heat input from the mantle from time to time as the reaction proceeds and the reflux rate diminishes. The reaction mixture is distilled under reduced pressure through a 13-cm. Vigreux column. The fraction boiling below 65 (50 mm.) is collected and washed

21、 with 50 ml. of water, then with 50-ml. portions of cold 1 N sodium hydroxide until the washings no longer contain phenol. The product is washed again with 50 ml. of water, dried over calcium chloride and redistilled, yielding 5160 g. (6475%) of neopentyl iodide, b.p. 5455 (55 mm.), nD21 1.4882.Ref:

22、 Organic Syntheses, Coll. Vol. 6, p.830; Vol. 51, p.44EXAMPLE 2:A 500-ml., two-necked, round-bottomed flask fitted with a reflux condenser equipped with a calcium chloride drying tube is charged with 124 g. (107 ml., 0.400 mole) of triphenyl phosphite and 85 g. (37 ml., 0.60 mole) of methyl iodide.

23、A thermometer of sufficient length extends into the liquid contents of the flask. The mixture is heated under gentle reflux with a heating mantle until the internal temperature has risen to about 120. At this point the mixture is dark and viscous. The flask is cooled, and 40 g. (0.40 mole) of cycloh

24、exanol is added to the oily methyltriphenoxyphosphonium iodide. The mixture is shaken gently until homogeneous and allowed to stand overnight at room temperature. The mixture is distilled through a 13-cm. Vigreux column, yielding 62.563 g. (7475%) of iodocyclohexane, b.p. 6668 (12 mm.), nD22 1.5475.

25、Ref: Organic Syntheses, Coll. Vol. 6, p.830; Vol. 51, p.44EXAMPLE 3:To a solution of methyltriphenoxyphosphonium iodide (2.3 mmol) in anhydrous dimethylformamide was added alcohol (2 mmol) at room temperature. After stirred for 18 h, the solvent was removed in vacuo and the residue was dissolved in

26、chloroform, extracted with 5% sodium thiosulfate, washed with water and dried. Direct crystallization from chloroform-hexane gave the iodide in 77% yield as needles.Ref: J. A. C. S. 1964, 2093-2095Ph3P, I2, imidazole体系特点：反应温度低，反应时间短，产率高EXAMPLE 1:To dry dichloromethane (4 mL) was added in order: trip

27、henylphosphine (1.21.5 mmol), imidazole (1.21.5 mmol) and iodine (1.21.5 mmol). A solution of the alcohol (1.0 mmol) in dry dichloromethane (1 mL) was added and the mixture was stirred at room temperature under argon for 0.53.0 h. The disappearance of the alcohol and formation of the alkyl iodide wa

28、s followed by TLC. When the reaction was complete, most of the solvent was removed in vacuo and the product was purified by passing it through a column of silica gel with pentane as solvent. Ref: Synthetic . Communications, 1990, 20, 10, 1473-1479EXAMPLE 2:Iodine (2.72 g, 10.7 mmol) was added in por

29、tions to a mixture of the alcohol (1.00 g, 5.14 mmol, finely powdered), triphenylphosphine (3.02 g, 11.5 mmol) and imidazole (1.59 g, 23.3 mmol) in toluene-acetonitrile (2:1 60 mL) stirred at 90oC. After 2h the mixture was cooled to room temperature. Water (50 mL) and toluene (20 mL) were added to t

30、he mixture which was then shaken vigorously and transferred to a separating funnel. The organic phase was extracted with water until only triphenylphosphine and triphenylphosphine oxide remained in the organic phase. The combined aqueous phase was washed with a small amount of toluene and then conce

31、ntrated. The residue was acetylated with acetic anhydride and pyridine at room temperature. When the acetylation was complete, the reaction mixture was concentrated and the residue dissolved in toluene. The toluene solution was extracted with water in water in order to remove imidazole impurities, d

32、ried and concentrated. The product was purified by chromatography on a short silica gel column to yield compound (1.41 g, 63%).Ref: J. C. S., Perkin Trans. 1, 1982, 681-683Mitsunobu 反应1967 年，Oyo Mitsunobu 报导了在三苯基膦（PPh3）和偶氮二甲酸二乙酯（DEAD）作用下酸和醇缩合成酯的新方法。当底物为仲醇的时候，与羟基相连的碳原子的构型会发生翻转。经过多年的研究和发展，形成了一大类合成方法，我们称之为Mitsunobu 反应。这类反应被广泛应用在有机合成，特别是天然产物的合成中。Mitsunobu 醇的翻转在Mitsunobu 反应中，DEAD 和三苯基膦首先生成一个活性的甜菜碱式中间体（betaine intermediate），这个活性中间体夺取作为亲核试剂的酸的质子并同时活化醇，随后经过SN2 取代，得到手性翻转的酯；将得到的酯水解，其净结果是醇的构型翻转。反应在很温和的条件下进行，通常反应温度是在0到