有机合成反应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范围越来越广泛,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R XPd(0)Z RZX = I, Br, OTf, etcZ = H, R, Ar, CN, CO2R, OR, OAc, NHAc, etc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PdⅡ配合物中间体；（b）配位插入（Cordination-insertion）:烯键插入Pd-R键的过程；（c）β-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：分子内反应和分子间反应。

第一篇该反应的报道是Heck 在1972年发表。

I+Pd(OAc)2 (20 mol%) n Bu N (1 eq) NMP, 100°C, 2hNolley, .; Heck, R. F.; Tetrahedron 1972, 37, 2320 Mori 和 Ban于1977年首次报道了分子内的Heck反应：Br N Ac CO2MeNAcCO2MePd(OAc)2 (2 mol%)PPh, DMFTMEDA (2 equaiv)125°C, 5h43%Indole product formed asresult of Pd-H isomerizationof product clefin Mori, M.; Ban, K.; Tetrahedron1977, 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。

2. 分子内的Heck 反应 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。

MeOOOMeIN ONCO 2Me OMeMeOOOMeN ONCO 2MeOMe Pd(PPh 3)4 (cat)NEt (12 eq)MeCN, 80°C, 10h90%Danishefsky, S. J. J. Am. Chem. Soc . 1993, 115, 6094该反应还被Danishefsky 应用到全合成Taxol 上。

OO Pd(PPh ) (1.1 eq)K2CO3, MeCN, 85°C49%Danishefsky, S. J. J. Am. Chem. Soc . 1996, 118, 2843分子内Heck 反应化生成环外双键示例OMeOMeON 2Me OMeN OMeOONCO 2MeOMePd(PPh ) , NEt (12eq)MeCN, 80℃, 10h12A stirred solution of 1(98 mg, mmol), triethylmine mL, mmol) and catalytic tetrakis(triphenylphosphine)palladium(0) (ca. 5 mg, 4 μmol) in 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 shiny layer of palladium metal upon completion of the reaction. The reaction mixture was cooled to room temperature; the reaction was quenched with aqueous NaHCO(15 mL), and the mixture was extracted with EtOAc (4×10 mL).3(1×15 mL), water (1 The organic extracts were washed with aqueous NaHSO3. Filtration, ×15 mL), and brine (1×15 mL) and dried over MgSO4 concentration, and purification of the orange residue by flash column chromatography (45:55 EtO/hexanes) gave 66 mg (90%) of 19 as a colorless2solid: mp 193-194 ℃; Rf = (8:2 Et2O/hexanes).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Overman 首先报道不对称Heck 反应。

ICO 2MePd(OAc)2 (3 mol%)(R)-BINAP (9 mol%)cyclohexene (6 mol%)74% (46% ee)Ag2CO3 (2 eq)NMP, 60°C1989, 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。

OOTfPd(OAc)2 (10 mol%)(R ,R )-DIOP (10 mol%)Et3N, C 6H 6, rt90% (45% ee)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。

MeOI N MeOOTIPSPd 2(dba)3-CHCl 3 (10 mol%)(S )-BINAP (23 mol%)PMP, DMA, 100°C3 M HClTHF, rtMeNH 3Cl, Et 3N LiAlH 4, THF, reflux84% (95% ee)(88%)(-)-esermethole1) BBr 3, CH 2Cl 2, rt 2) Na, Et 2O, MeNCO(31%)(-)-physostigmineMeNHCOMatsuura, T.; Overman, . 1998, 120, 6500分子内不对称Heck反应示例MeO INH OOTIPS10 % Pd(dba), 23 % (s)-BINAP, CHCl1,2,2,6,6-pentamethylpiperidine, DMA, 100 o C12A mixture of Pd2(dba)3·CHCl3(360 mg, mol), (s)-BINAP (504 mg, mol),and N,N-dimethylacetamide (DMA, 21 mL) was stirred at room temperaturefor 65 min. To the resulting orange solution was added a solution of compound 1 g, mol), 1,2,2,6,6-pentamethylpiperidine mL, 18 mmol), and DMA (18 mL), and the reaction was heated at 100 ℃ for 90 min. The resultdark solution was poured into half-saturated aqueous NaHCO3(100 mL) and extracted with ether (3 × 150 mL). The combined organic extracts werewashed 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 g, 94%) as a 98:2 mixture of geometric isomers:[α]25D –81o (c C6H6).多烯大环的合成分子内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。

IO OOPdCl2(MeCN)2 (100 mol%)NEt3, MeCN, 25°COOO55%16 member ring formationZeigler, F. Tetrahedron , 1981, 37, 4035也有多烯经过多次分子内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。

OTBSIR1, Pd(OAc)2 (30% mol)PPh (60% mol)2, TBAF, THFOverman, . 1999,121,5467Heck 反应用于合成大环多烯示例OTBSIi: Pd(OAc)2(30 mol%) PPh 3(60 mol%)3ii: TBAF, THFO O12A solution of vinyl iodide 1 (740 mg, mmol) and THF (75 mL) was degassed (Ar, evacuate-refill), and Ph 3P (107 mg, mmol), Ag 2CO 3 (410 mg, mmol), and Pd(OAc)2 (46 mg, 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 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 Ph 3P (107 mg, mmol), Ag 2CO 3 (410 mg, mmol), and Pd(OAc)2 (46 mg, mmol) were added, and 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 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 M solution in THF,mL) was added. The resulting solution was maintained at room temperaturefor 20 h and quenched with saturated aqueous NH4Cl (20 mL). The resultingmixture was extracted with CH2Cl2(3×20 mL), the combined organic layerswere dried (NaSO4), filtered and concentrated, and the residue was purified by flash chromatography (4:1 hexanes-EtOAc) to provide 370 mg (90%) of tricyclic allylic alcohol 2as a pale yellow oil: Rf=(5:1 hexanes-EtOAc).3. 分子间的Heck 反应常规分子间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。