1、經(jīng)典化學合成反應(yīng)標準操作1. 前言22. 分子內(nèi)的Heck反應(yīng)32.1 生成烯基取代的反應(yīng)32.1.1 分子內(nèi)Heck反應(yīng)化生成環(huán)外雙鍵示例42.2 形成季碳中心的反應(yīng)52.2.1 分子內(nèi)不對稱Heck反應(yīng)示例62.3 多烯大環(huán)的合成62.2.1 Heck反應(yīng)用于合成大環(huán)多烯示例73. 分子間的Heck 反應(yīng)83.1 常規(guī)分子間Heck反應(yīng)83.1.1 Pd(OAc)2-P(o-tol)3體系用于不飽和羧酸酯的Heck反應(yīng)標準操作三93.1.2 不飽和酮的Heck反應(yīng)標準操作103.1.3 雜環(huán)芳香鹵代物和不飽和羧酸酯的Heck反應(yīng)標準操作一103.1.4 雜環(huán)芳香鹵代物和不飽和羧酸酯的Hec

2、k反應(yīng)標準操作二103.1.5 芳香鹵代物和不飽和羧酸的Heck反應(yīng)合成反式3-芳基不飽和酸示例113.1.6 非共軛雙鍵Heck反應(yīng)示例113.2 不對稱分子間Heck反應(yīng)123.3 非常用離去基團的Heck反應(yīng)（Irina P. Beletskaya Chem. Rev. 2000, 100, 3009-3066）123.3.1 重氮鹽參與的Heck反應(yīng)示例133.3.2 酰氯參與的Heck反應(yīng)示例151. 前言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60年代末Heck 和Morizoki獨立發(fā)現(xiàn)該反應(yīng)以來,通過對催化劑和反應(yīng)條件的

3、不斷改進使其的應(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)的機理有一定的規(guī)律，通常認為反應(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)可以分為兩大類：分子內(nèi)反應(yīng)和分子間反應(yīng)。

4、第一篇該反應(yīng)的報道是Heck 在1972年發(fā)表。Nolley, J.P.; Heck, R. F.; Tetrahedron 1972, 37, 2320Mori 和 Ban于1977年首次報道了分子內(nèi)的Heck反應(yīng)：Mori, M.; Ban, K.; Tetrahedron 1977, 12, 1037經(jīng)過三十多年的發(fā)展，Heck反應(yīng)的應(yīng)用也越來越廣泛。每一類反應(yīng)根據(jù)其特點的不同由可以分成幾類。2. 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。目前已有合成的報道。Danishefsky, S. J. J

5、. Am. Chem. Soc. 1993, 115, 6094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, 28432.1.1 分子內(nèi)Heck反應(yīng)化生成環(huán)外雙鍵示例A stirred solution of 1 (98 mg, 0.19 mmol), triethylmine (0.32 mL, 2.3 mmol) and catalytic tetrakis(triphenylphosphine)palladium(0) (ca. 5 mg, 4 mol) in 2.4 mL of

6、acetonitrile was heated at 80 in a sealed tube under an argon atmosphere for 10 h. The reaction mixture turned dark orange after ca. 10 min, and the catalyst plated out on the walls of the tube as a shiny layer of palladium metal upon completion of the reaction. The reaction mixture was cooled to ro

7、om temperature; the reaction was quenched with aqueous NaHCO3(15 mL), and the mixture was extracted with EtOAc (4×10 mL). The organic extracts were washed with aqueous NaHSO3 (1×15 mL), water (1×15 mL), and brine (1×15 mL) and dried over MgSO4. Filtration, concentration, and puri

8、fication of the orange residue by flash column chromatography (45:55 Et2O/hexanes) gave 66 mg (90%) of 19 as a colorless solid: mp 193-194 ; Rf = 0.29 (8:2 Et2O/hexanes).2.2 形成季碳中心的反應(yīng)從20世紀80年代早期研究以來得到了廣泛的應(yīng)用。1989年，Shibasaki 和Overman 首先報道不對稱Heck反應(yīng)。J.Org.Chem. 1989, 54, 4738同一年，Overman及其工作組首先利用Heck 反應(yīng)合

9、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)不對稱Heck反應(yīng)示例A mixture of Pd2(dba)3·CHCl3 (360 mg, 0.347 mol), (s)-BINAP (504 mg, 0.809 mol), and N,N-dimethylacetamide (DMA, 21 mL) was stirred at room

10、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 poured into half-saturated aqueous NaHCO3 (1

11、00 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 a 98:2 mixture of geometric isomers:

12、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)建了二個環(huán)和二個季碳中心。Overman, L.E. J.Am.Chem.Soc., 1999,121,54672.2.1 Heck反應(yīng)用于合成大環(huán)多烯示例A solution of vinyl iodide 1 (740 m

13、g, 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 sealed tube for 12 h. A black suspensi

14、on 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 suspension was stirred in a sealed tube at 6

15、5 for an additional 6 h. The suspension was then cooled to room temperature and filtered through a plug of silica gel (1.5 cm×12 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 TBAF (1.0 M solution in THF,

16、 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 (3×20 mL), the combined organic layers were dried (NaSO4), filtered and concentrated, and the residue was pur

17、ified 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)。該類反應(yīng)在鹵代物中，鹵素的位的碳原子上不能有SP3雜化的氫原子。主要是因為這類鹵代物形成烷基鈀絡(luò)合物時，氫化鈀的消除反應(yīng)速度大于烯烴

18、的加成反應(yīng)，因此僅有消除產(chǎn)物。鹵代芳烴、鹵代雜環(huán)、鹵化芐、鹵代乙烯等都能較好的反應(yīng)。但其他一些鹵素的位的碳原子上沒有SP3雜化的氫原子存在的化合物由于種種原因也不能正常反應(yīng)，例如：鹵代甲烷、鹵代乙酸乙酯、苯甲酰甲基溴等。該類反應(yīng)常用碘代物和溴代物為反應(yīng)底物，碘代物相對溴代物反應(yīng)活性要高。氯代物反應(yīng)活性很差（幾乎不反應(yīng)或者收率很低）。在取代碘代物參與的反應(yīng)中，取代基可以很廣泛的使用，但鄰位的苯甲?；〈饣锖茈y反應(yīng)。當有強烈供電子基團時，芳基溴參與的反應(yīng)收率也很低。其主要原因是在反應(yīng)中膦配體被季化與鹵代物被還原。當使用P(o-tol)3作為配體時，可以有效的避免配體的季化。另外，當有強烈的供電

19、子基團時，烯烴的活性也很重要。低活性烯烴參與的反應(yīng)收率也較低。決定烯烴活性的主要因素是烯烴雙鍵碳原子取代基的大小和數(shù)目。一般情況下，取代基越大，數(shù)目越多，反應(yīng)速度越小，收率越低。當一些烯烴反應(yīng)活性較差時，通常可以得到鹵化物二聚的副產(chǎn)物。一般說來，共軛二烯和, -不飽和羰基化合物的活性高于立體相似的單烯化合物。例如鹵代烯烴與丙烯酸的反應(yīng)速度遠大于丙烯腈，而丙烯腈的活性又高于丙烯縮醛。在大多數(shù)情況下，Pd-H的消除符合Curtin-Hammett動力學控制規(guī)則，即過渡態(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

20、-Horner反應(yīng)。但由于存在異構(gòu)化，熱力學控制時常常產(chǎn)生二者的混合物，從而導致例外的情況出現(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)標準操作三A mixture of 3-bromoquinoline (2.08 g, 10.0 mmol), methyl acrylate (1.08 g, 12

21、.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 diluted with DCM (60 ML) and distilled water (30 ML).The organic

22、 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 by recrystallization with EtOAc and hexanes gave an off-white

23、crystalline solid (1.82 g; 85percent):3.1.2 不飽和酮的Heck反應(yīng)標準操作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 heated under N2 at 100 oC for 6-12 h. The reaction mixture wa

24、s 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 reduced pressure purification with column chromatography to give

25、the product.Note: 有時可以分離到雙鍵還原的產(chǎn)物。3.1.3 雜環(huán)芳香鹵代物和不飽和羧酸酯的Heck反應(yīng)標準操作一A suspension of ArBr (68.4 mmol), Pd(dppf)Cl2 (5 g, 6.84 mmol), tetrabutylammonium iodide (30 g, 82 mmol) and K2CO3 (28 g, 205 mmol) in N,N-dimethylformide (130 mL) was degassed via three vacuum/nitrogen ingress cycle, and then added m

26、ethyl acrylate (17.6 g, 205 mmol), the mixture was stirred at 100 oC overnight. To the mixture was added water; the aqueous layer was extracted with Et2O (3×100 ml). The combined organic phases were washed by brine, dried over MgSO4, filtered and concentrated. The residue was purified by column

27、 chromatography to afford the product (, yield50%).3.1.4 雜環(huán)芳香鹵代物和不飽和羧酸酯的Heck反應(yīng)標準操作二A suspension of ArBr (170mmol), Pd(OAc)2 (1.9g, 8.5mmol), tetrabutylammonium iodide (55.0g, 170mmol) and KOAc (5.01g, 511mmol) in N,N-dimethylformide (200 mL) was degassed via three vacuum/nitrogen ingress cycle, and

28、then added methyl acrylate (46.0mL, 511mmol), the mixture was stirred at 100 oC overnight. To the mixture was added water; the aqueous layer was extracted with Et2O (3×300 mL). The combined organic phases were washed by brine, dried over MgSO4, filtered and concentrated. The residue was purifie

29、d by column chromatography to afford the product (15 g, yield 50%). Note: Pd(OAc)2的質(zhì)量有時是實驗成敗的關(guān)鍵，3.1.5 芳香鹵代物和不飽和羧酸的Heck反應(yīng)合成反式3-芳基不飽和酸示例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

30、steam 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)示例Typical procedure for the preparation of ci

31、nnamaldehyde: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 a

32、t 90oC. 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 (sil

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

34、作堿時，1a的對應(yīng)選擇性為69%ee。3.3 非常用離去基團的Heck反應(yīng)（Irina P. Beletskaya Chem. Rev. 2000, 100, 3009-3066）Beller等人報道了重氮鹽參與的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

35、, 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（0.005 mol%）。Spencer, A. J. Organomet. Chem. 1984, 265, 323將酸酐應(yīng)用于Heck反應(yīng)時20世紀末才發(fā)現(xiàn)的，它的優(yōu)點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)示例Table 1. Heck Reaction of p-Methoxyphenyldiazonium Tereafluoroborate With Acrylic Acid

36、 EstersEntrySolventRCatalyst (mol%)Yield1MethanolCH3Pd/Ca (1)952EthanolC2H5Pd/C a (1)983EthanolC2H5Pd/Al2O3 a (1)894EthanolC2H5Pd/BaSO4 a (1)945DMSOC8H17Pd/C a (1)676CH3CNC8H17Pd/C a (1)<57TolueneC8H17Pd/C a (1)<582-EH b (1)C8H17Pd/C a (1)<59EthanolC2H5Pd/C c (1)31a The Palladium is 5% of w

37、eight on the corresponding catalyst support. b 2-EH = 2-ethylhexan-1-ol. c Already used catalyst.Beller, M.; Kuehlein, K. Synlett. 1995, 441General procedure for the synthesis of cinnamic acid esters: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 0°C. Then the reaction mixture is heated to 60&#