Appel-Reaction-and-Mitsunobu-Reaction

1、Appel Reacti on and Mits un obu Reacti onAppel 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。PPh 3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

2、物，則最后一步生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(lái)。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ⅰ?可編輯修改-65醇和有機(jī)磷氯化物的反應(yīng)三苯基膦氯化物，如Ph3PX 2, PH 3P+CX 3X-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

3、和六氯代丙酮（HCA ）復(fù)合物和 Ph3P/CCl 4 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/CCl 4 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。夕 IxOH PXP/HCA（90% ）12HHHH尸OHPh 3P/HCA ,/(94%)13DH0C-r.t., 10 minD* H（ 99% 構(gòu)型翻轉(zhuǎn)）Cl-可編輯修改-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n體系的羥基氯置換。Example A:

4、A dry, 300-ml., three-necked flaskis equipped with amagn etic stirri ngandreflux con de nserbar(to which is attached a Drierite-filled dryi ng tube ) andcharged with 90 ml. of carbon tetrachloride and 15.42 g. of geraniol(0.1001mole) . To this solution is added and34.09 g. (0.1301 mole) of triphe ny

5、lphosphi nethe stirred react ion mixture isheated un der reflux for 1 hour. Thismixture is allowed to cool to room temperature; drypentane is added (100ml.) , and stirring is continued for an additional 5 minutes.The triphe ny Iphosphi ne oxide precipitate is filtered and washed with50ml. of pen ta

6、ne. The solve nt is removed from the comb ined filtrate with arotary evaporatorunder water aspirator pressure at room temperature. Distillation ofthe residue through a2-cm. Vigreux columnattached to ashort-path distillation apparatusprovides13.0 4.0 g. (75 -81% ) of geranylchloride , b.p. 47 Z9 0 (0

7、.4 mm.), n23 D = 1.4794.-可編輯修改-Example B:1 2To a cooled 25 ml round-bottom flask containing 1 (50 mg, 0.16 mmol) andPh3P (51 mg, 0.2 mmol) was added hexachloroacet one (HCA, 0.05 ml, 0.3 mmol)in 1 ml of CH2Cl2. The reaction mixture was allowed to come to room temperatureand stirred overnight. The mi

8、xture was subjected to purificati on by flash silica gelcolu mn chromatography, with elution first by hexane to remove the HCA and thenby 5% ethyl acetate/hexa nes 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, PH 3P+CX3X-以及亞磷酸三苯酯溴化物如(PhO ) 3PX 2、( 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

9、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(lèi)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(guò)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)，生成溴化物，同時(shí)發(fā)生構(gòu)型翻轉(zhuǎn)-可編輯修改-r PPh 3 + X 24 Ph 3PX2L Ph 3PX2+ ROH - ROP +Ph 3X-+ HXRX + Ph 3PO-PPh 3 + CX 4 -Ph3P+ CCl3 CPh3P+ CCl3Cl- + ROH- a RX + Ph 3PO + CHX 3(PhO) 3 P + RX- (PhO

10、) 2P+ RX -R 1X + PhOH + PhjP R、 (PhO ) 2P+ RX- + R 1 OHO O-Ph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OH(63%)Ph3 PBr 2, DMFBr15-45C(79% ee) a D 20 -26.02 (76% -81% ee)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。nExample

11、A :PPh 3, CBr 4RRRNBS/Ph 3 P or (PhO) 3PA(95%)-THF,r.t.,1hHOBr- 可編輯修改 -To a soluti onof 1 (4 g, 22.5 mmol) in CH2CI2 (50 ml) at roomtemperaturewasaddedCBr 4 (11.2 g, 34 mmol) followed bytriphe ny Iphosphi ne (8.8 g, 33 mmol). The react ion mixture was allowedto stir for 2.5 h, and the solve nt was r

12、emoved un der vacuum.Chromatography (30% EtOAc-hexa nes)afforded 5.91 g (98%) ofproduct 2 as an off-white solid.Example BHOJ*BrPPh 3 , CBr 4CO2 BnCH 2Cl2N CO Bn2BocBocThe alcohol (5.34 g, 16.7 mmol) and CBr4 (16.6 g, 50 mmol) weredissolved in 100 ml of dichloromethane. This solution was treated with

13、solid triphe ny Iphosphi ne (13.1 g, 50 mmol) over a 10 min period. Thissolution was allowed to stir for 18 h, and then 10 ml of ethanol wasadded. After 2 h this solution was treated with 100 ml of Et2O bydropwise addition over a 0.5 h period. The mixture was filtered, and thefiltrate and washings w

14、ere trhen concentratedand purified by flashchromatography to give 4.79 g (74% yield) of the title compo und. Thismaterial recrystallized (Et2O/hexa ne) on sta nding to give mp 87-88°CExample C-可編輯修改-Ph3P, B 2, Py, DCM-OH-15-20CBrIn a well-ve ntilated hood, a 2-L, three-n ecked, roun d-bottomed

15、flask, equippedwith a magnetic stirrer, thermometer, dropping funnel, and a reflux condenser, ischarged under nitrogenwith 327 g (1.24 mol) oftriphe ny Iphosph ine,and 1.24 L of an hydrous dichlorometha ne . Thesoluti on is vigorously stirred un der acet on e-dry ice cooli ng, as 199 g (64.1 ml,1.25

16、 mol) of bromine is added over a period of 0.5 hr at- 30C°to-15°C under nitrogen. After an additional 15 min of stirring, a mixture of 116 g (1.18mol) of 1-cyclopropylcyclopropa nol a nd 93.5 g (95.6 ml, 1.18 mol) of an hydrouspyridi ne is added dropwise at-15°C over a period of 2hour

17、s. The mixture is stirred at 20° C for an additional24 hours undernitrogen. The reflux condenser and the dropping funnel are removed. The flask isimmersed in an oil bath and conn ected to a 2-L, two-n ecked, round-bottomed flaskvia a 90 ° angle glass tube. The second flask iscooled with ac

18、et on e-dryice. All the volatile material is bulb-to-bulbdistilled, at first under water-aspirator vacuum and 30C oil bath temperature,° andthe n un der further reduced pressure (0.1 mm) with a 100C oil bath°.Thedistillation is continued until the temperature in the first flask reaches 80&

19、#176;C. Thereceiver flask is allowed to warm to 20°C, andthe solve nt is removed by distillati on at atmospheric pressure using a 30-cmVigreux colu mn. The residue is distilled un der reduced pressure to give 117.1 g(62%) of 1-bromo-1-cyclopropylcyclopropa ne.-可編輯修改-醇和有機(jī)磷碘化物的反應(yīng)-可編輯修改-(PhO) 3P,

20、CH 3I 體系EXAMPLE 1:CH3CHCH 3 - CH 2OH + CH 3I + (C 6H5O)3PCH3CH3CH 3CH 2I + (C 6H5O)2POCH 3 + C 6H5 OH3A 500-ml.,two-necked,round-bottomed flask fitted with a refluxcondenser equipped with a calcium chloride drying tube is charged with 136 g. (115ml., 0.439 mole) of triphenyl phosphite, 35.2 g. (0.40

21、0 mole) of neopentyl alcohol,and 85 g. (37 ml., 0.60 mole) ofmethyl iodide. Athermometer of sufficie nt len gth exte nds into the liquid contents of the flask. Themixture is heated under gentle reflux with an electric heating mantle until thetemperature of the refluxing liquid rises from its initial

22、 value of 75 -800 to about130 °a nd the mixture darke ns and begi ns to fume. The time required is about 24hours. It is n ecessary to adjust the heat in put from the man tle from time to time asthe react ion proceeds and the reflux rate diminishes. The reaction mixture isdistilledunderreduced p

23、ressure through a 13-cm. Vigreux colu mn. The fracti on boili ng below 650 (50 mm.) is collected and washed with 50 ml. of water, then with 50-ml. portions ofcold 1 N sodium hydroxide until the washings no Ion ger contain phe nol. Theproduct is washed aga in with 50 ml. of water, dried over calcium

24、chloride andredistilled, yielding 51-60 g. (64 -75%) ofneopentyl iodide, b.p. 54-°55 (55 mm.), nD21 1.4882.-可編輯修改-Ref:Orga nic Syn theses, Coll. Vol. 6, p.830; Vol. 51, p.44-可編輯修改-EXAMPLE 2:CH 3I + (C 6H5O ) 3PA (C 6 H5O) 3PCH 3I(C6H5O) 3PCH 3I +(C 6H5O) 2POCH 3 + C 6 H5OHA 500-ml.,two-necked,r

25、ound-bottomedflask fitted with a refluxcondenser equipped with a calcium chloride drying tube is charged with124 g. (107 ml., 0.400 mole) of triphenyl phosphite and 85 g. (37 ml., 0.60mole) of methyl iodide. A thermometer of sufficient length extends intothe liquid contents of the flask. The mixture

26、 is heated under gentle refluxwith a heating mantle until the internal temperature has risen to about120 ° At this point the mixture is dark and viscous. The flask is cooled,and 40 g. (0.40 mole) of cyclohexa nol is added to the oilymethyltriphenoxyphosphoniumiodide. The mixture is shaken gentl

27、yun til homoge neous and allowed to sta nd over ni ght at room temperature.The mixture is distilled through a 13-cm. Vigreux column, yielding62.5 -63 g. (74 5%) of iodocyclohexane, b.p. 66 -68° (12 mm.), nD22 1.5475.Ref: Orga nic Syn theses, Coll. Vol. 6, p.830; Vol. 51, p.44EXAMPLE 3:-可編輯修改-(C

28、 6H5O) 3 PCH 3IDMF, R.T.,18 hTo a solutionof methyltriphenoxyphosphonium aniodide (2.3 mmol) inhydrous dimethylformamide was added alcohol (2 mmol)atroomtemperature. After stirred for 18 h, the solve nt was removed in vacuoand the residue was dissolved in chloroform, extracted with 5% sodiumthiosulf

29、ate, washed with water and dried. Direct crystallizationfromchloroform-hexane gave the iodide in 77% yield as needles.Ref: J. A. C. S. 1964, 2093-20953P, 12, imidazole 體系Ph特點(diǎn)：反應(yīng)溫度低，反應(yīng)時(shí)間短，產(chǎn)率高EXAMPLE 1:OHPh 3P/imidazole/l 2CH 2 CI2, R.T.,0.53h,6098%To dry dichlorometha ne (4 mL) was added in order: tr

30、iphe ny Iphosph ine(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) wasadded and the mixture was stirred at room temperature un der argon for0.53.0 h.The disappeara nee of the alcohol and formati on of the alkyl-可編輯修改-

31、iodide was followed by TLC.Whe n the react ion was complete, most of thesolve nt was removed in vacuo and the product waspurified by pass ing it through a colu mn of silica gel with pentane as solve nt.Ref: Synthetic . Communications, 1990, 20, 10, 1473-1479EXAMPLE 2:OH1) Ph 3P/imidazole/l 2tolue ne

32、-aceton itrilek. o OMe90 o CHO j-OH1OH2) acetic an hydrideIodine (2.72 g, 10.7 mmol) was added in portions to a mixture of the alcohol (1.00 g,5.14 mmol, fin ely powdered), triphe ny Iphosphi ne (3.02 g,11.5 mmol) and imidazole (1.59 g, 23.3 mmol) in toluene-acetonitrile (2:160 mL) stirred at 90oC.

33、After 2h the mixture was cooled to room temperature. Water(50 mL) and toluene (20 mL) were added to the mixture which was then shakenvigorouslyand transferred to aseparating funnel. The organic phase was extracted with water until only triphe nyIphosphi ne and triphe ny Iphosph ine oxide rema ined i

34、n the orga nic phase.Thecomb ined aqueous phase was washed with a smallamount of tolue ne and the n concen trated.The residue was acetylatedwith acetic an hydride and pyrid ine at room temperature.Whe n theacetylati on was complete, the react ion mixture was concen trated and the-可編輯修改-residue disso

35、lved in toluene. The toluene solution was extracted with water in water in order to remove imidazole impurities, dried and concen trated. The product was purified by chromatography on a short silica gel colu mn to yield compo und (1.41 g, 63%).Ref: J. C. S., Perkin Trans. 1, 1982, 681-683Mitsu nobu反

36、應(yīng)1967 年 , Oyo Mitsunobu報(bào)導(dǎo)了在三苯基膦( PPh 3) 和偶氮二甲酸二乙酯( DEAD ) 作用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)Ph3PDEAD經(jīng)過(guò)多年的研究和發(fā)展，形成了一大類(lèi)合成方法，我們稱(chēng)之為Mits unobu反應(yīng)。這類(lèi)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。Mitsu nobu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 ( betai ne in termediate) ，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(guò)SN2 取代，得到手

37、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)。-可編輯修改-EtOjC pa 3EtEtO 2C CO 2EtN-NN_N?+ i 二(DEAD)Ph3Pbetaine不會(huì)影響反應(yīng)。但親核試劑質(zhì)子的pKa 值必須小于甜菜堿式中間體( betaine反應(yīng)在很溫和的條件下進(jìn)行，通常反應(yīng)溫度是在0 C 到室溫，大部分基團(tuán)都in termediate ) 的 pKa 值，否則親核試劑的質(zhì)子不能被中間體(beta inein termediate ) 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 也用作溶最早將 Mitsun

38、obu 手性翻轉(zhuǎn)用于天然產(chǎn)物的合成的一個(gè)例子如下，只需步就能實(shí)現(xiàn)。RCO 2H97%.R = HPhP, DEAD. THF90%, R = Ph99%.R = CH 2Ph-可編輯修改-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。1, PNBA. Ph 3 PDEAD, PhCH 3/Et 2 O2. KCOaMeOHF*92% OverTwo StepsOMep-硝基苯甲酸（ PNBA ）還能有效地抑制副反應(yīng)：醇的消除。所以

39、，在Mitsu nobu反應(yīng)中，通常使用p-硝基苯甲酸（ PNBA ）。PhCO 2HH,N CO 9Me*Ph 3P, DEADCbz' 丫 2H Cbz" N'OHHPNBA-Cbz V 2Ph 3P. DEADO 2CC 6H 4pNO 253%86%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-可編輯修改-0riBusP, PhHL 60C°O O、 N幾N二N幾II(TMAD)99%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。HOyCOpHy0Ph3P T DEADTsOH .LIGHN 'B OC訃皿叱°N- Bx HTFA.O CNH,40%_尺VCO2HNH 2磺酸類(lèi)化合物也能參與Mitsunobu反應(yīng)，在生成磺酸酯的同時(shí)得到手性翻轉(zhuǎn)的產(chǎn)物。1 RSOH. 曰屮PhjP,DIAD, PhH82%, R = j>Tol2, NaOH: HCl34%, R = MeMsQH. THFPh3 P. DEAD-可編輯修改