Heck反應(yīng)及金屬催化偶聯(lián)反應(yīng)課件

1、Heck 反應(yīng)南京航空航天大學(xué) 仿生結(jié)構(gòu)與材料防護(hù)研究所汝杰過渡金屬催化的交叉偶聯(lián)反應(yīng)Transition Metal Catalyzed Cross CouplingThe formation of carboncarbon bonds is a fundamentalreaction in organic synthesis the efficiency of which hasinterested organic chemists for a long time ago. Arylarylbond formation has been known for more than a cent

2、ury andwas one of the first reactions involving a transition metal.1Modern synthetic chemistry is also sustained by the useof transition-metal catalysts as powerful tools for carboncarbon bond-forming processes.2 Among these,carboncarbon coupling reactions through the activationof carbonhydrogen bon

3、ds,3 as well as addition reactions,4have experienced an increasing interest in the preparation ofmolecules, the access to which is not so straightforwardusing other methodologies. On the other hand, thetransition-metal catalysed carboncarbon bond formationdeveloped in the 1970s represented a milesto

4、ne in syntheticorganic chemistry that allowed the cross coupling ofsubstrates in ways that would have previously been thoughtimpossible2010 Nobel prize 瑞典皇家科學(xué)院說，這三名科學(xué)家因在有機(jī)合成領(lǐng)域中鈀催化交叉偶聯(lián)反應(yīng)方面的卓越研究獲獎(jiǎng)。這一成果廣泛應(yīng)用于制藥、電子工業(yè)和先進(jìn)材料等領(lǐng)域，可以使人類造出復(fù)雜的有機(jī)分子。赫克,79歲，美國(guó)特拉華大學(xué)名譽(yù)教授；根岸榮一,75歲,美國(guó)普渡大學(xué)化學(xué)教授；鈴木彰,80歲,日本札幌北海道大學(xué)教授。Glaser

5、 (Hay) CouplingSuzuki CouplingSonogashira ReactionAmination ReactionStille reactionThe Kumada Coupling was the first Pd or Ni-catalyzed cross coupling reaction, developed in 1972. Kumada reactionNegishi reactionFukuyama Coupling Heck reaction 通常把在堿性條件下鈀催化的芳基或乙烯基鹵代物和活性烯烴之間的偶聯(lián)反應(yīng)稱為Heck反應(yīng)。自從20世紀(jì)60年代末Hec

6、k 和Morizoki獨(dú)立發(fā)現(xiàn)該反應(yīng)以來,通過對(duì)催化劑和反應(yīng)條件的不斷改進(jìn)使其的應(yīng)用范圍越來越廣泛,使該反應(yīng)已經(jīng)成為構(gòu)成C-C鍵的重要反應(yīng)之一。另外，Heck反應(yīng)具有很好的Trans選擇性 研究表明，Heck反應(yīng)的機(jī)理有一定的規(guī)律，通常認(rèn)為反應(yīng)共分四步：（a）氧化加成（Oxidative addition）: RX (R為烯基或芳基，X=I TfO Br Cl)與Pd0L2的加成，形成Pd配合物中間體；（b）配位插入 （Cordination-insertion）:烯鍵插入Pd-R鍵的過程； （c）-H的消除； （d）催化劑的再生：加堿催化使重新得到Pd0L2。 總的說來，Heck反應(yīng)可以分為

7、兩大類：分子內(nèi)反應(yīng)和分子間反應(yīng)。第一篇該反應(yīng)的報(bào)道是Heck 在1972年發(fā)表的。Nolley, J.P.; Heck, R. F.; Tetrahedron 1972, 37, 2320Mori 和 Ban于1977年首次報(bào)道了分子內(nèi)的Heck反應(yīng)：Mori, M.; Ban, K.; Tetrahedron 1977, 12, 10372. 分子內(nèi)的Heck反應(yīng)2.1 生成烯基取代的反應(yīng)該類反應(yīng)主要用于生成環(huán)外雙鍵。環(huán)外雙鍵是合成上一大難題，該反應(yīng)成功的應(yīng)用具有重大意義。目前已有合成的報(bào)道。Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 60

8、94該反應(yīng)還被Danishefsky應(yīng)用到全合成Taxol上。Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 2843（紫杉醇） 分子內(nèi)Heck反應(yīng)化生成環(huán)外雙鍵A stirred solution of 1, triethylmine and catalytic tetrakispalladium(0) in 2.4 mL of acetonitrile was heated at 80 in a sealed tube under an argon atmosphere for 10 h. The reaction mixture turne

9、d dark orange after ca10 minand the catalyst plated out on the walls of the tube as a shiny layer of palladium metal upon completion of the reactionThe reaction mixture was cooled to room temperaturethe reaction was quenched with aqueous NaHCO3andthe mixture was extracted with EtOAc The organic extr

10、acts were washed with aqueous NaHSO3 water and brine and dried over MgSO4 Filtrationconcentrationand purification of the orange residue by flash column chromatography gave 66mg of19 as acolorless solidmp 193-194 Rf = 0.292.2 形成季碳中心的反應(yīng) 從20世紀(jì)80年代早期研究以來得到了廣泛的應(yīng)用。1989年，Shibasaki 和Overman 首先報(bào)道不對(duì)稱Heck反應(yīng)。J.

11、Org.Chem. 1989, 54, 4738 同一年，Overman及其工作組首先利用Heck 反應(yīng)合成了手性季碳原子。J.Org.Chem.1989,54,5846 像天然產(chǎn)物physostigmine的合成，成功的運(yùn)用和Heck反應(yīng)構(gòu)成手性的季碳中心。Matsuura, T.; Overman, L.E. J.Am.Chem.Soc. 1998, 120, 65002.2.1 分子內(nèi)不對(duì)稱Heck反應(yīng)A mixture of Pd2(dba)3CHCl3 (360 mg, 0.347 mol), (s)-BINAP (504 mg, 0.809 mol), and N,N-dimeth

12、ylacetamide (DMA, 21 mL) was stirred at room temperature for 65 min. To the resulting orange solution was added a solution of compound 1 (1.82 g, 3.51 mol), 1,2,2,6,6-pentamethylpiperidine (3.2 mL, 18 mmol), and DMA (18 mL), and the reaction was heated at 100 for 90 min. The result dark solution was

13、 poured into half-saturated aqueous NaHCO3 (100 mL) and extracted with ether (3 150 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4), and concentrated, and the residue was purified by sgc (9:1 1:1 hexane-EtOAc) to give oxindole enoxysilane compound 2 (1.29 g, 94%) as

14、 a 98:2 mixture of geometric isomers: 25D 81o (c 0.61 C6H6).2.3 多烯大環(huán)的合成 分子內(nèi)Heck反應(yīng)形成的多烯大環(huán)化合物(大于13)。Zeigler就利用Heck反應(yīng)成功合成十六元環(huán)的大環(huán)多烯化合物Zeigler, F. Tetrahedron, 1981, 37, 4035 也有多烯經(jīng)過多次分子內(nèi)Heck反應(yīng)，一步構(gòu)建多個(gè)碳碳鍵和多元環(huán)。Overman 就成功應(yīng)用Heck反應(yīng)一步構(gòu)建了二個(gè)環(huán)和二個(gè)季碳中心。Overman, L.E. J.Am.Chem.Soc., 1999,121,54672.2.1 Heck反應(yīng)用于合成大環(huán)多烯

15、A solution of vinyl iodide 1 (740 mg, 1.35 mmol) and THF (75 mL) was degassed (Ar, evacuate-refill), and Ph3P (107 mg, 0.41 mmol), Ag2CO3 (410 mg, 1.5 mmol), and Pd(OAc)2 (46 mg, 0.20 mmol) were added. The resulting suspension was stirred at room temperature for 15 min and then heated at 65 in a sea

16、led tube for 12 h. A black suspension resulted after 10-20 min at 65 . After GC analysis of a filtered aliquot showed that the reaction had not proceeded to completion, additional Ph3P (107 mg, 0.41 mmol), Ag2CO3 (410 mg, 1.5 mmol), and Pd(OAc)2 (46 mg, 0.20 mmol) were added, and the black suspensio

17、n was stirred in a sealed tube at 65 for an additional 6 h. The suspension was then cooled to room temperature and filtered through a plug of silica gel (1.5 cm12 cm, EtOAc), and the filtrate was concentrated to give the crude Heck product as a yellow oil.This sample was dissolved in THF (4 mL), and

18、 TBAF (1.0 M solution in THF, 2.0 mL) was added. The resulting solution was maintained at room temperature for 20 h and quenched with saturated aqueous NH4Cl (20 mL). The resulting mixture was extracted with CH2Cl2 (320 mL), the combined organic layers were dried (NaSO4), filtered and concentrated,

19、and the residue was purified by flash chromatography (4:1 hexanes-EtOAc) to provide 370 mg (90%) of tricyclic allylic alcohol 2 as a pale yellow oil: Rf=0.25(5:1 hexanes-EtOAc).3. 分子間的Heck 反應(yīng)3.1 常規(guī)分子間Heck反應(yīng) 端基烯烴與鹵代芳香烴發(fā)生分子間Heck反應(yīng)，是研究最早的一類反應(yīng)。這類反應(yīng)已經(jīng)成為芳烴烷基化重要反應(yīng)。 在大多數(shù)情況下，Pd-H的消除符合Curtin-Hammett動(dòng)力學(xué)控制規(guī)則，即過

20、渡態(tài)的能量反應(yīng)了順反異構(gòu)體的比例。一般情況下，除非R特別?。ㄈ?CN）,反式異構(gòu)體是主要產(chǎn)物，（見下例）。其選擇性甚至超過Wittig-Horner反應(yīng)。但由于存在異構(gòu)化，熱力學(xué)控制時(shí)常常產(chǎn)生二者的混合物，從而導(dǎo)致例外的情況出現(xiàn)。 而烯丙基醇與鹵代化合物發(fā)生分子間Heck反應(yīng)，通過一系列消去-加成過渡態(tài)，可以得到羰基化合物。目前，我們應(yīng)用該反應(yīng)最多的是芳基鹵代物和, -不飽和羰基化合物之間的偶聯(lián)反應(yīng)，通過催化劑、配體的選擇及反應(yīng)條件的優(yōu)化，一般都能以合適的收率得到Trans偶聯(lián)產(chǎn)物。3.1.1 Pd(OAc)2-P(o-tol)3體系用于不飽和羧酸酯的Heck反應(yīng)A mixture of 3-

21、bromoquinoline (2.08 g, 10.0 mmol), methyl acrylate (1.08 g, 12.5 mmol), palladium acetate (23.6 mg, 0.1 mmol), tri(o-tolyl)phosphine (0.122 g, 0.4 mmol) and triethylamine (3.62 g, 35.8 mmol) was heated under argon in a heavy-walled Pyrex tube at 100.deg. C. for 6 h.The cooled reaction mixture was d

22、iluted with DCM (60 ML) and distilled water (30 ML).The organic layer was washed with distilled water (3*25 ML).The aqueous layer was extracted with DCM (25 ML).The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a pale yellow solid.Purification

23、 by recrystallization with EtOAc and hexanes gave an off-white crystalline solid (1.82 g; 85percent):3.1.2 不飽和酮的Heck反應(yīng)A mixture of 4-bromotoluene (10.0 mmol), Cyclohex-2-enone (10 mmol), palladium acetate (0.1 -0.5 mmol), tri(o-tolyl) (0.2-1 mmol, 催化劑的2-4倍的量) and DIEA (30 mmol) in DMF (30 mL) was he

24、ated under N2 at 100 oC for 6-12 h. The reaction mixture was cooled, diluted with 50 mL of water and extracted with ether (2 x 50 mL). The combined organic portion was washed with brine solution, dried over anhydrous magnesium sulfate and finally filtered. Evaporatation of the volatiles under reduce

25、d pressure purification with column chromatography to give the product.Note: 有時(shí)可以分離到雙鍵還原的產(chǎn)物。3.1.5 芳香鹵代物和不飽和羧酸的Heck反應(yīng)合成反式3-芳基不飽和酸A solution of compound 1 (2.8 g, 10 mmol), compound 2 (0.9 mL, 12.5 mmol), Pd(OAc)2 (0.022g, 0.01 mmol), Et3N (3.5 mL, 25 mmol) and 4 mL acetonitrile was heated in a steam

26、bath for 1 hour. After the reaction mixture had been cooled, it was diluted with 250 mL 10% aq. HCl. The solid formed was collected by filtration and re-crystallized from ethanol to give compound 3 (1.86 g, yield 82%), mp 215-.6 非共軛雙鍵Heck反應(yīng)Typical procedure for the preparation of cinnamalde

27、hyde:To a stirred solution of p-iodoanisole (0.117 g, 0.5 mmol) in 2.0 mL of DMF were added acrolein diethyl acetal (0.229 mL, 1.5 mmol), nBu4NOAc (0.302 g, 1.0 mmol0, K2CO3 (0.104 g, 0.75 mmol), KCl (0.037 g, 0.5 mmol), and Pd(OAc)2 (0.003 g, 0.015 mmol). The mixture was stirred for 1.5 h at 90oC.

28、After cooling, 2 N HCl was slowly added and the reaction mixture was stirred ar room temperature for 10 min. Then, it was diluted with ether and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (silica gel,

29、 35 g; n-hexane/ethylacetate 90/10 v/v) to give 0.071 g (88%) of p-methoxycinnamaldehyde.3.2 不對(duì)稱分子間Heck反應(yīng) 1992年，Tamio Hayashi等報(bào)道了手性鈀催化的環(huán)狀烯烴的不對(duì)稱Heck芳基化反應(yīng)。 Tamio Hayashi, Pure & Appl. Chem., 1992, 64(3), 421-427 堿對(duì)芳基花產(chǎn)物的對(duì)應(yīng)選擇性有一定的影響。 例如, 用高位阻的強(qiáng)堿性1，8-雙（N,N-二甲氨基）萘?xí)r，其1a的對(duì)應(yīng)選擇性超過96%ee。 若用2，6-二甲基吡啶作堿時(shí)，1a的對(duì)應(yīng)選

30、擇性為69%ee。3.3 非常用離去基團(tuán)的Heck反應(yīng) Beller等人報(bào)道了重氮鹽參與的Heck反應(yīng)不需要膦催化劑和胺，條件溫和，是很實(shí)用的芳基化反應(yīng)。Beller, M.; Kuehlein, K. Synlett. 1995, 441 碘鹽參與的Heck反應(yīng)條件也比較溫和，用水作溶劑反應(yīng)較快，適用于一些懼怕激烈反應(yīng)條件的底物。對(duì)于二芳基碘鹽的Heck反應(yīng)，一般常溫下得到一取代的產(chǎn)物，回流條件下得到二取代產(chǎn)物。Kang, S.-K. J. Org. Chem. 1996, 61, 2604 酰氯參與的Heck反應(yīng)一般在非極性溶劑中使用弱堿即可，無需膦催化劑，而且所需鈀催化劑用量極少（0.0

31、05 mol%）。Spencer, A. J. Organomet. Chem. 1984, 265, 323 將酸酐應(yīng)用于Heck反應(yīng)時(shí)20世紀(jì)末才發(fā)現(xiàn)的，它的優(yōu)點(diǎn)在于不需要任何堿的存在。Guertler, C. Chem. Eur. J. 1999, 5, 31073.3.1 重氮鹽參與的Heck反應(yīng)30 mmol of corresponding diazonium salt and 60 mmol of acrylic acid ester are suspended in 40 mL of the solvent. Subsequently, 0.6 mmol of palladium on activated charcoal (5% weight) is added at 0C. Then the reaction mixture is heated to 60C in the course of 1 hour and stirred for 12 hours at this temperature. After cooling to room temperature, the catalyst is filtered off and washed with the solvent. The solvent is evaporated in vacuo a