AppelReactionandMitsunobuReaction

1、Appel 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

2、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起的副反应。三苯基膦和六氯代丙酮（HCA）复合物和Ph3P/CCl

3、4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 reflux condenser (to which is attached

4、 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 mixture is allowed to cool to room

5、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 water aspirator pressure at room

6、 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 (50 mg, 0.16 mmol) and Ph3P

7、 (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 first by hexane to remove t

8、he 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成物或相应的亚磷酸酯，后经溴素负离子的SN2反应，生成

9、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 CBr4 (11.2 g, 34 mmol) follow

10、ed 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) and CBr4 (16.6 g, 50 mmol)

11、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 Et2O by dropwise addition o

12、ver 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 well-ventilated hood, a 2-L

13、, 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 under acetone-dry ice cool

14、ing, as 199 g (64.1 ml, 1.25 mol) of bromine is added over a period of 0.5 hr at 30°C to 15°C 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 dropwise at 15

15、6;C over a period of 2 hours. The mixture is stirred at 20°C 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 se

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

17、n the first flask reaches 80°C. The receiver flask is allowed to warm to 20°C, 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

18、物的反应(PhO)3P, CH3I体系EXAMPLE 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

19、 iodide. A thermometer of sufficient 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 an

20、d begins to fume. The time required is 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 be

21、low 65° (50 mm.) is collected and washed 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

22、 iodide, b.p. 5455° (55 mm.), nD21 1.4882.Ref: 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 phosphi

23、te and 85 g. (37 ml., 0.60 mole) of methyl iodide. 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 visc

24、ous. The flask is cooled, and 40 g. (0.40 mole) of cyclohexanol 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. (74

25、75%) of iodocyclohexane, b.p. 6668° (12 mm.), nD22 1.5475.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

26、 solvent was removed in vacuo and the residue was dissolved in 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E

27、XAMPLE 1:To dry dichloromethane (4 mL) was added in order: triphenylphosphine (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 di

28、sappearance of the alcohol and formation of the alkyl iodide was 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,

29、 1473-1479EXAMPLE 2:Iodine (2.72 g, 10.7 mmol) was added in portions 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

30、 temperature. Water (50 mL) and toluene (20 mL) were added to the 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

31、 phase was washed with a small amount of toluene and then concentrated. 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

32、 with water in water in order to remove imidazole impurities, dried 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

33、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到室温，大部分基团都不会影响反应。但亲核试剂质子的p

34、Ka值必须小于甜菜碱式中间体（betaine intermediate）的pKa值，否则亲核试剂的质子不能被中间体（betaine intermediate）夺取，反应不能进行。低极性的溶剂有利于反应，通常用四氢呋喃，乙醚，二氯甲烷和甲苯作为溶剂，有时候乙酸乙酯，乙腈和DMF也用作溶剂。最早将Mitsunobu 手性翻转用于天然产物的合成的一个例子如下，只需一步就能实现。1991 年，化学家 Martin 和 Dodge 发现用p-硝基苯甲酸（PNBA）作为亲核试剂对立体位阻较大的醇的翻转更有效。Buszek和Jeong据此合成了Octalatin A和B的前体。p-硝基苯甲酸（PNBA）还能

35、有效地抑制副反应：醇的消除。所以，在Mitsunobu 反应中，通常使用p-硝基苯甲酸（PNBA）。Tsunoda等发现，对于位阻较大的醇，TMAD(N,N,N,N-tetramethylazodicarboxamide)和三丁基膦的体系效果比较好。分子内的Mitsunobu反应为内酯的合成提供了一个有效的方法。Verderas等利用这个方法合成了一系列的氨基酸。磺酸类化合物也能参与Mitsunobu 反应，在生成磺酸酯的同时得到手性翻转的产物。Mitsunobu 醇的构型翻转合成方法示例A 250-mL, three-necked, round-bottomed flask is equip

36、ped with a stirring bar, nitrogeninlet, rubber septum, and thermometer. The flask is charged with 3.00 g of (1R, 2S,5R)-()-menthol (19.2 mmol), 12.9 g of 4-nitrobenzoic acid (77.2 mmol), 20.1 g oftriphenylphosphine (PPh3) (76.6 mmol), and 150 mL of tetrahydrofuran. The flask isimmersed in an ice bat

37、h, and 12.1 mL of diethyl azodicarboxylate (77 mmol) is added dropwise at a rate such that the temperature of the reaction mixture is maintained below 10°C.Upon completion of the addition, the flask is removed from the ice bath and the solution is allowed to stir at room temperature overnight (

38、14 hr) and subsequently at 40°C for 3 hr. The reaction mixture is cooled to room temperature, diluted with 150 mL of ether, and washed twice with 100 mL portions of saturated aqueous sodium bicarbonate solution. The aqueous layers are combined and back-extracted with 100 mL of ether. The combin

39、ed organic layers are dried over sodium sulfate. Excess solvent and other volatile reaction components are completely removed under reduced pressure initially on a rotary evaporator and then under high vacuum (approximately 0.2 mm for 3 hr at 30°C). The resulting semi-solid is suspended in 40 m

40、L of ether and the suspension is allowed to stand at room temperature overnight. The mixture is stirred while 20 mL of hexanes is slowly added. The resulting white solid is filtered under vacuum and the filter cake is washed with 200 mL of 50% (v/v) ether-hexanes. The solvent is removed from the fil

41、trate on a rotary evaporator under reduced pressure to give a yellow oil that is dissolved in 10 mL of methylene chloride and diluted with 40 mL of 8% ether-hexanes. The solution is applied to a flash chromatography column and eluted with 8% ether-hexanes to give 5.03 g (85.6%) of pure nitrobenzoate

42、 ester as a white crystalline solid.Mitsunobu 醚化反应在Mitsunobu 反应中，羟基也可以作为亲核试剂参与SN2 取代，结果是生成醚。但通常只限于酚羟基和pKa<13 的羟基，否则反应不能进行。如下面苯酚的葡糖苷化，两步收率达到55。如果作为亲电试剂的羟基活性足够高，或反应生成稳定的环状产物，对于较低活性的羟基，Mitsunobu 醚化反应也能进行。Tsunoda 等发现TMAD能促进反应进行，从而得到较高的产率。Mitsunobu 醚的合成方法示例 A solution of benzyl alcohol (0.200 g, 1.85

43、mmol), 4-hydroxybenzaldehyde (0.226 g,1.85 mmol), and PPh3(0.582 g, 2.22 mmol) was stirred in dry THF (20 mL) at 0 °C under a nitrogen atmosphere. To this mixture was added dropwise DIAD (0.44 mL, 2.22 mmol) over a period of 5 min, and the reaction was monitored by TLC. After complete disappear

44、ance of starting material (1 h), the solvent was evaporated under reduced pressure and the resulting oil purified by flash column chromatography (hexane/AcOEt, 8/2). Phenyl ether (0.297 g, 76%)was finally obtained as a white powder after precipitation from CH2Cl2/petroleum ether.Mitsunobu 氨基取代反应氨基化合

45、物也可以作为Mitsunobu 反应中的亲核试剂，取代羟基，生成取代的氨基化合物。同样，参与反应的胺必须有足够的酸性（pKa<13），能被PPh3/DEAD体系夺去质子。酰胺，磺酰胺，亚胺和叠氮化合物都可以参与反应。Weinreb 用这种方法，在经过连续两次的Mitsunobu 反应后，合成了天然产物SarainA的主环。近年来，相继发展了一些用于Mitsunobu 氨基取代反应的试剂，这些试剂在取代后，再脱去保护基而得到各种氨基化合物。Hart和Campbell报导2-(trimethylsilyl)ethylsulfonyl（TES）保护的Boc酰胺，在Mitsunobu 氨基取代后

46、，可以去保护生成Boc 保护的胺或胺的盐酸盐。Fukuyama报导硝基苯磺酰胺类化合物在经过Mitsunobu氨基取代后，能方便地用苯硫酚脱去磺酰基，得到仲胺。Bach 和Kather 报导Fmoc 保护的磺酰胺在Mitsunobu 氨基取代后，能直接脱去Fmoc 而得到磺酰胺。酰胺也能作为Mitsunobu 氨基取代反应的底物。比如下面的分子内氨基取代，得到氮杂环化合物。一个从Gabriel 氨基合成衍生过来的合成伯胺的方法，在Mitsunobu 氨基取代中用邻苯二甲酰亚胺作为亲核试剂，然后肼解，便得到手性翻转的伯胺。另一个合成伯胺的方法是在Mitsunobu 反应中用叠氮取代羟基，然后还原

47、，便能得到伯胺。由于叠氮酸使用不方便，一个替代方法是用diarylphosphoryl azide (DPPA)作为叠氮基团的来源。Taber 和Decher 通过这个方法得到了相应的叠氮化合物。Myers报导磺酰肼与-羟基取代炔经过Mitsunobu氨基取代反应，生成的产物不稳定，马上分解为丙二烯化合物，这是一个制备丙二烯化合物的比较便捷的方法。Mitsunobu利用苯磺酰胺合成胺方法示例N-Boc p-toluenesulfonamide (88mg, 0.322 mmol) was dissolved in dry THF (3 mL) and PPh3 (168 mg, 0.645 m

48、mol) was added. The solution was stirred under nitrogen and the alcohol (0.215 mmol) was added followed by DEAD (0.083 mL, 0.53 mmol). The mixture was stirred at room temperature for 3 h, concentrated in vacuo and the residue was purified by flash column chromatography (P: E 4: 1) to give the produc

49、t (62%).Mitsunobu 利用DPPA 合成伯胺方法示例 To a cooled solution (-5oC) of DIAD (7.9 g, 93 mmol) in THF (5 mL) was added the substituted alchol (7.06 g, 18.7 mmol) and PPh3 (10.3 g, 39.1 mmol). After 15 min, diphenyl phosphorazidate (DPPA, 12.86 g, 46.77mmol) was added and the reaction mixture was allowed to

50、warm to room temperature. After stirring overnight, the solvent was removed in vacuo to give a yellow oil. The crude material was purified by flash column chromatograghy(2:1,PE/Tol) to give the desired product (7.28 g, 91%) as a colorless oil.Mitsunobu 分子内关环合成相应的环状胺方法示例To a solution of substituted p

51、roline (33.6 g, 0.1 mol) and PPh3 (31.5 g, 0.12 mol) in THF(200 mL) was dropped a solution of DEAD (18.8 mL, 0.12 mmol) in dry THF (50 mL) at ice bath. The reaction mixture was allowed to warm to stirred 20oC for 2 h. The filtrate was evaporated and stirred with EA (100 mL), and the product was collected by filtration (20.66 g,74%). The solvent was removed under reduced pre