有机合成经典反应Heck反应.docx

1、有机合成经典反应Heck反应经典化学合成反应标准操作1. 前言通常把在碱性条件下钯催化的芳基或乙烯基卤代物和活性烯烃之间的偶联反应称为Heck反应。自从20世纪60年代末Heck 和Morizoki独立发现该反应以来,通过对催化剂和反应条件的不断改进使其的应用围越来越广泛,使该反应已经成为构成C-C键的重要反应之一。另外，Heck反应具有很好的Trans选择性研究表明，Heck反应的机理有一定的规律，通常认为反应共分四步：（a）氧化加成（Oxidative addition）: RX (R为烯基或芳基，X=I TfO Br Cl)与Pd0L2的加成，形成Pd配合物中间体；（b）配位插入 （Co

2、rdination-insertion）:烯键插入Pd-R键的过程； （c）-H的消除； （d）催化剂的再生：加碱催化使重新得到Pd0L2。总的说来，Heck反应可以分为两大类：分子反应和分子间反应。第一篇该反应的报道是Heck 在1972年发表。Nolley, J.P.; Heck, R. F.; Tetrahedron 1972, 37, 2320Mori 和 Ban于1977年首次报道了分子的Heck反应：Mori, M.; Ban, K.; Tetrahedron 1977, 12, 1037经过三十多年的发展，Heck反应的应用也越来越广泛。每一类反应根据其特点的不同由可以分成几类。

3、2. 分子的Heck反应2.1 生成烯基取代的反应该类反应主要用于生成环外双键。环外双键是合成上一大难题，该反应成功的应用具有重大意义。目前已有合成的报道。Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 6094该反应还被Danishefsky应用到全合成Taxol上。Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 28432.1.1 分子Heck反应化生成环外双键示例A stirred solution of 1 (98 mg, 0.19 mmol), triethylmine (0.32 mL,

4、 2.3 mmol) and catalytic tetrakis(triphenylphosphine)palladium(0) (ca. 5 mg, 4 mol) in 2.4 mL of 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 shin

5、y layer of palladium metal upon completion of the reaction. The reaction mixture was cooled to room temperature; the reaction was quenched with aqueous NaHCO3(15 mL), and the mixture was extracted with EtOAc (410 mL). The organic extracts were washed with aqueous NaHSO3 (115 mL), water (115 mL), and

6、 brine (115 mL) and dried over MgSO4. Filtration, concentration, and purification 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 形成季碳中心的反应从20世纪80年代早期研究以来得到了广泛的应用。1989年，Shibasaki 和Ove

7、rman 首先报道不对称Heck反应。J.Org.Chem. 1989, 54, 4738同一年，Overman及其工作组首先利用Heck 反应合成了手性季碳原子。J.Org.Chem.1989,54,5846 像天然产物physostigmine的合成，成功的运用和Heck反应构成手性的季碳中心。Matsuura, T.; Overman, L.E. J.Am.Chem.Soc. 1998, 120, 65002.2.1 分子不对称Heck反应示例A mixture of Pd2(dba)3CHCl3 (360 mg, 0.347 mol), (s)-BINAP (504 mg, 0.809

8、 mol), and N,N-dimethylacetamide (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 res

9、ult dark solution was 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 compou

10、nd 2 (1.29 g, 94%) as a 98:2 mixture of geometric isomers: 25D 81o (c 0.61 C6H6).2.3 多烯大环的合成分子Heck 反应形成的多烯大环化合物(大于13)。Zeigler 就利用Heck反应成功合成十六元环的大环多烯化合物。Zeigler, F. Tetrahedron, 1981, 37, 4035也有多烯经过多次分子Heck反应，一步构建多个碳碳键和多元环。Overman 就成功应用Heck反应一步构建了二个环和二个季碳中心。Overman, L.E. J.Am.Chem.Soc., 1999,121,5467

11、2.2.1 Heck反应用于合成大环多烯示例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

12、 heated at 65 in a sealed 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, a

13、nd the black suspension 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 dissol

14、ved in THF (4 mL), and 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), filte

15、red and concentrated, 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. 分子间的Heck 反应3.1 常规分子间Heck反应端基烯烃与卤代芳香烃发生分子间Heck反应，是研究最早的一类反应。这类反应已经成为芳烃烷基化重要反应。该类反应在卤代物中，卤素的位的碳原子上不能

16、有SP3杂化的氢原子。主要是因为这类卤代物形成烷基钯络合物时，氢化钯的消除反应速度大于烯烃的加成反应，因此仅有消除产物。卤代芳烃、卤代杂环、卤化苄、卤代乙烯等都能较好的反应。但其他一些卤素的位的碳原子上没有SP3杂化的氢原子存在的化合物由于种种原因也不能正常反应，例如：卤代甲烷、卤代乙酸乙酯、苯甲酰甲基溴等。该类反应常用碘代物和溴代物为反应底物，碘代物相对溴代物反应活性要高。氯代物反应活性很差（几乎不反应或者收率很低）。在取代碘代物参与的反应中，取代基可以很广泛的使用，但邻位的苯甲酰基取代碘化物很难反应。当有强烈供电子基团时，芳基溴参与的反应收率也很低。其主要原因是在反应中膦配体被季化与卤代物被还原。当使用P(o-tol)3作为配体时，可以有效的避免配体的季化。另外，当有强烈的