Appel-Reaction-and-Mitsunobu-Reaction

1、 Appel Reaction and Mitsunobu ReactionAppel 反應(yīng)Appel反應(yīng)，用三苯基膦和四氯化碳將醇轉(zhuǎn)化為氯代烴。此反應(yīng)是用于引入鹵原子的一種較為溫和的方法。伯醇、仲醇和多數(shù)叔醇都能順利發(fā)生反應(yīng)。用四溴化碳或溴作為鹵原子源，或者用碘甲烷或碘，可得到相應(yīng)的溴代烴和碘代烴。首先三苯基膦與四氯化碳生成鏻正離子和三氯甲基負(fù)離子離子對(duì)，三氯甲基負(fù)離子從醇奪取質(zhì)子，生成氯仿，同時(shí)醇轉(zhuǎn)化為烷氧負(fù)離子。烷氧負(fù)離子對(duì)鏻正離子進(jìn)行親核取代，得到含 P-O 鍵的中間體 (5)和氯離子，然后氯離子對(duì) (5)進(jìn)行親核進(jìn)攻，產(chǎn)生三苯基氧膦和產(chǎn)物氯代烴 (6)。如果以叔醇為底物，則最后一步生

2、成氯代烴和三苯基氧膦為 SN1 機(jī)理。反應(yīng)的推動(dòng)力是固體三苯基氧膦的生成，它從反應(yīng)混合物中分離出來。其中含有鍵能較強(qiáng)的 P=O 雙鍵，利于反應(yīng)進(jìn)行?？梢赃@樣認(rèn)為，四氯化碳中的一個(gè)氯在反應(yīng)后轉(zhuǎn)移到氯代烴中，自身接受醇的羥基氫，生成氯仿。醇的羥基氧則被三苯基膦接受，三苯基膦變?yōu)槿交蹯?。醇和有機(jī)磷氯化物的反應(yīng)三苯基膦氯化物，如Ph3PX2, PH3P+CX3X- 以及亞磷酸三苯酯氯化物如(PhO)3PX2、(PhO)3P+RX-，在和醇進(jìn)行氯置換反應(yīng)，具有活性大，反應(yīng)條件溫和等特點(diǎn)。由于反應(yīng)中產(chǎn)生的氯化氫很少，因此不容易發(fā)生氯化氫引起的副反應(yīng)。三苯基膦和六氯代丙酮（HCA）復(fù)合物和Ph3P/CC

3、l4相似，也能將光學(xué)活性的烯丙醇在溫和條件下轉(zhuǎn)化成為構(gòu)型翻轉(zhuǎn)的烯丙氯代物，而且不發(fā)生異構(gòu)、重排等副反應(yīng)。這個(gè)試劑比Ph3P/CCl4更溫和，反應(yīng)迅速，特別適宜于用其他方法易引起重排的烯丙醇。此外，三苯膦或亞磷酸酯和N-氯代酰胺組成的復(fù)合氯化劑與上述試劑相似，但特別適宜于對(duì)酸不穩(wěn)定的醇或者是甾體醇的氯置換反應(yīng)，也可用于缺電子的體系的羥基氯置換。Example A: A dry, 300-ml., three-necked flask is equipped with a magnetic stirring bar and reflux condenser (to which is attache

4、d 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 roo

6、m 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 Ph3

7、P (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

8、the HCA and then by 5% ethyl acetate/hexanes to give 49 mg (93%) of 2.醇和有機(jī)磷溴化物的反應(yīng)三苯膦溴化物，如Ph3PX2, PH3P+CX3X- 以及亞磷酸三苯酯溴化物如(PhO)3PX2、(PhO)3P+RX-，在和醇進(jìn)行溴置換反應(yīng)是，具有活性大，反應(yīng)條件溫和等特點(diǎn)。由于反應(yīng)中產(chǎn)生的溴化氫很少，因此不容易發(fā)生溴化氫引起的副反應(yīng)。這兩類試劑均可由三苯膦或亞磷酸三苯酯和溴素或溴代烷直接制得，不經(jīng)過分離純化即可和醇進(jìn)行反應(yīng)。其反應(yīng)歷程是這些試劑和醇反應(yīng)生成醇烷氧基取代的三苯膦加成物或相應(yīng)的亞磷酸酯，后經(jīng)溴素負(fù)離子的SN2反應(yīng)，生

9、成溴化物，同時(shí)發(fā)生構(gòu)型翻轉(zhuǎn)。這些試劑的應(yīng)用很廣泛，常以DMF或HMPTA作為溶劑進(jìn)行溴置換反應(yīng)，也可在較溫和的條件下將光學(xué)活性的仲醇轉(zhuǎn)化成構(gòu)型翻轉(zhuǎn)的溴代烴，或?qū)δ承┰谒嵝詶l件下不穩(wěn)定的化合物進(jìn)行溴化。此外，三苯膦或亞磷酸酯和N-溴代酰胺組成的復(fù)合溴化劑與上述試劑相似，但特別適宜于對(duì)酸不穩(wěn)定的醇或者是甾體醇的溴置換反應(yīng)，也可用于缺電子的體系的羥基溴置換。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) follo

10、wed 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

12、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 well-ventilated hood, a 2-

13、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 under acetone-dry ice coo

14、ling, 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、76;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 s

16、econd 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

17、in 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.醇和有機(jī)磷碘

18、化物的反應(yīng)(PhO)3P, CH3I體系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 methy

19、l 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 a

20、nd 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 b

21、elow 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 neopenty

22、l 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 phosph

23、ite 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 vis

24、cous. 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. (7

25、475%) 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, th

26、e 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體系特點(diǎn)：反應(yīng)溫度低，反應(yīng)時(shí)間短，產(chǎn)率高

27、EXAMPLE 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 d

28、isappearance 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 roo

30、m 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 aqueou

31、s 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 extracte

32、d 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 反應(yīng)1967 年，Oyo Mitsunobu 報(bào)導(dǎo)了在三苯基膦（PPh3）和偶氮二甲酸二乙酯（DEAD）作用

33、下酸和醇縮合成酯的新方法。當(dāng)?shù)孜餅橹俅嫉臅r(shí)候，與羥基相連的碳原子的構(gòu)型會(huì)發(fā)生翻轉(zhuǎn)。經(jīng)過多年的研究和發(fā)展，形成了一大類合成方法，我們稱之為Mitsunobu 反應(yīng)。這類反應(yīng)被廣泛應(yīng)用在有機(jī)合成，特別是天然產(chǎn)物的合成中。Mitsunobu 醇的翻轉(zhuǎn)在Mitsunobu 反應(yīng)中，DEAD 和三苯基膦首先生成一個(gè)活性的甜菜堿式中間體（betaine intermediate），這個(gè)活性中間體奪取作為親核試劑的酸的質(zhì)子并同時(shí)活化醇，隨后經(jīng)過SN2 取代，得到手性翻轉(zhuǎn)的酯；將得到的酯水解，其凈結(jié)果是醇的構(gòu)型翻轉(zhuǎn)。反應(yīng)在很溫和的條件下進(jìn)行，通常反應(yīng)溫度是在0到室溫，大部分基團(tuán)都不會(huì)影響反應(yīng)。但親核試劑質(zhì)子的

34、pKa值必須小于甜菜堿式中間體（betaine intermediate）的pKa值，否則親核試劑的質(zhì)子不能被中間體（betaine intermediate）奪取，反應(yīng)不能進(jìn)行。低極性的溶劑有利于反應(yīng)，通常用四氫呋喃，乙醚，二氯甲烷和甲苯作為溶劑，有時(shí)候乙酸乙酯，乙腈和DMF也用作溶劑。最早將Mitsunobu 手性翻轉(zhuǎn)用于天然產(chǎn)物的合成的一個(gè)例子如下，只需一步就能實(shí)現(xiàn)。1991 年，化學(xué)家 Martin 和 Dodge 發(fā)現(xiàn)用p-硝基苯甲酸（PNBA）作為親核試劑對(duì)立體位阻較大的醇的翻轉(zhuǎn)更有效。Buszek和Jeong據(jù)此合成了Octalatin A和B的前體。p-硝基苯甲酸（PNBA）還

35、能有效地抑制副反應(yīng)：醇的消除。所以，在Mitsunobu 反應(yīng)中，通常使用p-硝基苯甲酸（PNBA）。Tsunoda等發(fā)現(xiàn)，對(duì)于位阻較大的醇，TMAD(N,N,N,N-tetramethylazodicarboxamide)和三丁基膦的體系效果比較好。分子內(nèi)的Mitsunobu反應(yīng)為內(nèi)酯的合成提供了一個(gè)有效的方法。Verderas等利用這個(gè)方法合成了一系列的氨基酸?；撬犷惢衔镆材軈⑴cMitsunobu 反應(yīng)，在生成磺酸酯的同時(shí)得到手性翻轉(zhuǎn)的產(chǎn)物。Mitsunobu 醇的構(gòu)型翻轉(zhuǎn)合成方法示例A 250-mL, three-necked, round-bottomed flask is equi

36、pped 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 ba

37、th, 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 combi

39、ned 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

40、mL 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 fi

41、ltrate 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 nitrobenzoat

42、e ester as a white crystalline solid.Mitsunobu 醚化反應(yīng)在Mitsunobu 反應(yīng)中，羥基也可以作為親核試劑參與SN2 取代，結(jié)果是生成醚。但通常只限于酚羥基和pKa<13 的羥基，否則反應(yīng)不能進(jìn)行。如下面苯酚的葡糖苷化，兩步收率達(dá)到55。如果作為親電試劑的羥基活性足夠高，或反應(yīng)生成穩(wěn)定的環(huán)狀產(chǎn)物，對(duì)于較低活性的羥基，Mitsunobu 醚化反應(yīng)也能進(jìn)行。Tsunoda 等發(fā)現(xiàn)TMAD能促進(jìn)反應(yīng)進(jìn)行，從而得到較高的產(chǎn)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 disappea

44、rance 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 氨基取代反應(yīng)氨基化

45、合物也可以作為Mitsunobu 反應(yīng)中的親核試劑，取代羥基，生成取代的氨基化合物。同樣，參與反應(yīng)的胺必須有足夠的酸性（pKa<13），能被PPh3/DEAD體系奪去質(zhì)子。酰胺，磺酰胺，亞胺和疊氮化合物都可以參與反應(yīng)。Weinreb 用這種方法，在經(jīng)過連續(xù)兩次的Mitsunobu 反應(yīng)后，合成了天然產(chǎn)物SarainA的主環(huán)。近年來，相繼發(fā)展了一些用于Mitsunobu 氨基取代反應(yīng)的試劑，這些試劑在取代后，再脫去保護(hù)基而得到各種氨基化合物。Hart和Campbell報(bào)導(dǎo)2-(trimethylsilyl)ethylsulfonyl（TES）保護(hù)的Boc酰胺，在Mitsunobu 氨基取代

46、后，可以去保護(hù)生成Boc 保護(hù)的胺或胺的鹽酸鹽。Fukuyama報(bào)導(dǎo)硝基苯磺酰胺類化合物在經(jīng)過Mitsunobu氨基取代后，能方便地用苯硫酚脫去磺?；?，得到仲胺。Bach 和Kather 報(bào)導(dǎo)Fmoc 保護(hù)的磺酰胺在Mitsunobu 氨基取代后，能直接脫去Fmoc 而得到磺酰胺。酰胺也能作為Mitsunobu 氨基取代反應(yīng)的底物。比如下面的分子內(nèi)氨基取代，得到氮雜環(huán)化合物。一個(gè)從Gabriel 氨基合成衍生過來的合成伯胺的方法，在Mitsunobu 氨基取代中用鄰苯二甲酰亞胺作為親核試劑，然后肼解，便得到手性翻轉(zhuǎn)的伯胺。另一個(gè)合成伯胺的方法是在Mitsunobu 反應(yīng)中用疊氮取代羥基，然后還

47、原，便能得到伯胺。由于疊氮酸使用不方便，一個(gè)替代方法是用diarylphosphoryl azide (DPPA)作為疊氮基團(tuán)的來源。Taber 和Decher 通過這個(gè)方法得到了相應(yīng)的疊氮化合物。Myers報(bào)導(dǎo)磺酰肼與-羥基取代炔經(jīng)過Mitsunobu氨基取代反應(yīng)，生成的產(chǎn)物不穩(wěn)定，馬上分解為丙二烯化合物，這是一個(gè)制備丙二烯化合物的比較便捷的方法。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

48、mmol) 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 produ

49、ct (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 分子內(nèi)關(guān)環(huán)合成相應(yīng)的環(huán)狀胺方法示例To a solution of substituted

51、proline (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 pressure and the crude oil was purified bycolumn chromatograghy to afford the desired product (27.3 g, 86%).Mitsunobu 硫代