有机合成反应Heck反应.docx

经典化学合成反应标准操作1. 前言12. 分子内的Heck反应22.1生成烯基取代的反应22.1.1分子内Heck反应化生成环外双键示例32.2形成季碳中心的反应42.2.1分子内不对称Heck反应示例52.3多烯大环的合成52.2.1 Heck反应用于合成大环多烯示例63. 分子间的Heck反应73.1常规分子间Heck反应73.1.1 Pd(OAc)2-P(o-tol)3体系用于不饱和羧酸酯的Heck反应标准操作三.83.1.2不饱和酮的Heck反应标准操作93.1.3杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作一93.1.4杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作二93.1.5芳香卤代物和不饱和羧酸的Heck反应合成反式3-芳基不饱和酸示例.103.1.6非共轭双键Heck反应示例103.2不对称分子间Heck反应113.3 非常用离去基团的 Heck 反应(Irina P. Beletskaya Chem. Rev. 2000, 100,3009-3066)113.3.1重氮盐参与的Heck反应示例123.3.2酰氯参与的Heck反应示例141.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Pd(0)rX R、.：W Z厂ZX = 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 PdoL2 的加成， 形成Pdl配合物中间体；(b)配位插入(Cordination-insertion):烯键插入Pd-R键的过总的说来，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。a1Pd(OAc)2 (20 mol%) n Bu3N (1 eq)NMP, 100°C, 2hNolley, J.P.; Heck, R. F.;Tetrahedron 1972, 37, 2320Pd(OAc)2 (2 mol%)PPh3, DMFTMEDA (2 equaiv) 125°C, 5h43%Mori和Ban于1977年首次报道了分子内的Heck反应:Indole product formed as result of Pd-H isomerization of product clefinMori, 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。2.分子内的Heck反应2.1生成烯基取代的反应90%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。Pd(PPh3)4 (cat) NEt3(12 eq)MeCN, 80°C, 10hDanishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 6094该反应还被Danishefsky应用到全合成Taxol上。OPd(PPh3)4 (1.1 eq)K2CO3, MeCN, 85°COTBSO49%Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 28432.1.1分子内Heck反应化生成环外双键示例12A stirred solution of 1 (98 mg, 0.19 mmol), triethylmine (0.32 mL, 2.3 mmol) andcatalytic tetrakis(triphenylphosphine)palladium(0) (ca. 5 mg, 4 冲ol) in 2.4 mL of acetonitrile was heated at 80 °C 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 aqueousNaHCO3(15 mL), and the mixture was extracted with EtOAc (4X10 mL). The organic extracts were washed with aqueous NaHSO 3 (1X 15 mL), water (1 X 15 mL), and brine (1 X 15 mL) and dried over MgSO4. Filtration, concentration, and purification of the orange residue by flash column chromatography (45:55 Et 2O/hexanes) gave 66 mg (90%) of 19 as a colorless solid: mp 193-194 C; 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Overman 首先报道不对称Heck反应。CO_Me.Pd(OAc)2 (3 mol%) (R)-BINAP (9 mol%) cyclohexene (6 mol%)Ag2CO3 (2 eq) NMP, 60°CH74% (46% ee)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。OPd(OAc)2 (10 mol%) (R,R)-D|Op (10 mol%)曰3N，C6H6, rtO90% (45% ee)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。MePMP, DMA, 100°CPd2(dba)3-CHCl3 (10 mol%) (S)-BINAP (23 mol%)3 M HClTHF, rtMeNH3Cl, Et3N LiAlH4, THF, reflux (88%)(-)-esermethole1) BBr3, CH2Cl2, rt2) Na, Et2O, MeNCO(31%)Matsuura, T.; Overman, L.E. J.Am.Chem.Soc. 1998,120, 6500iA mixture of Pd 2(dba)3 CHC13 (360 mg, 0.347 mol), (s)-BINAP (504 mg, 0.809 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 °C for 90 min. The result dark solution was poured into half-saturated aqueous NaHCO3 (100 mL) and extracted with ether (3 X 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 一 1:1 hexane-EtOAc) to give oxindole enoxysilane compound 2 (1.29 g, 94%) as a 98:2 mixture of geometric isomers: a25D -81。(c 0.61 C6H6).2.3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。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。1, Pd(OAc)2 (30% mol) PPh3 (60% mol)Ag2CO3, THF,2, TBAF, THFOHOverman, L.E. J.Am.Chem.Soc., 1999,121,5467i: Pd(OAc)2(30 mol%) PPh/60 mol%)AgCO3, THF, 65C ii: TBAF, THF1MeOH2A 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), Ag 2CO3 (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 °C in a sealed tube for 12 h. A black suspension resulted after 10-20 min at 65 C. 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 65 C for an additional 6 h. The suspension was then cooled to room temperature and filtered through a plug of silica gel (1.5 cm X 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, 2.0 mL) was added. The resulting solution was maintained at room temperature for 20 h and quenched with saturated aqueous NH 4Cl (20 mL). The resulting mixture was extracted with CH 2Cl2 (3 X 20 mL), the combined organic layers were dried (NaSO 4), filtered 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P位的碳原子上不能有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P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、苯甲酰甲基漠等。该类反应常用碘代物和漠代 物为反应底物，碘代物相对漠代物反应活性要高。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，芳基漠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，当有强烈的供电子基团时，烯烃的活性也很重要。低活性烯烃参与 的反应收率也较低。决定烯烃活性的主要因素是烯烃双键碳原子取代基的大小和数目。一般情况下，取 代基越大，数目越多，反应速度越小，收率越低。当一些烯烃反应活性较差时，通常可 以得到卤化物二聚的副产物。一般说来，共轭二烯和a, P-不饱和羰基化合物的活性高于 立体相似的单烯化合物。例如卤代烯烃与丙烯酸的反应速度远大于丙烯腊，而丙烯腊的 活性又高于丙烯缩醛。在大多数情况下，Pd-H的消除符合Curtin-Hammett动力学控制规则，即过渡态的 能量反应了顺反异构体的比例。一般情况下，除非R特别小（如-CN）,反式异构体是 主要产物，（见下例）。其选择性甚至超过Wittig-Horner反应。但由于存在异构化，热力 学控制时常常产生二者的混合物，从而导致例外的情况出现。fO2CH3CH广CHCO2CH3 + J丁 *唤啊P°T "丫 N°2Et3N, 100CVch2=chco2ch3 +Pd(OAc)2, POTEt3N, CH3CN, 100°C'%,.-co2ch3而烯丙基醇与卤代化合物发生分子间Heck反应，通过一系列消去-加成过渡态，可以得到羰基化合物。CH2=C(CH3)CH2OH+Pd(OAc)2, PPh3 广NaHCO3, DMF, 100°C目前，我们应用该反应最多的是芳基卤代物和a,。-不饱和羰基化合物之间的偶联反 应，通过催化剂、配体的选择及反应条件的优化，一般都能以合适的收率得到Trans偶 联产物。3.1.1 Pd(OAc)2-P(o-tol)3体系用于不饱和羧酸酯的Heck反应标准操作三ch2=chco2ch3 +BrPd(OAc)2, POT Et3N, CH3CN, 100°CCO2CHA mixture of 3-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 diluted 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 by recrystallization with EtOAc and hexanes gave an off-white crystalline solid (1.82 g; 85percent):Br+Pd(OAcPOT, DMF, DIEAA 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,催化剂的 2-4 倍的量)and DIEA (30 mmol) inDMF (30 mL) was heated under N 2 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 reduced pressure purification with column chromatography to give the product.Note:有时可以分离到双键还原的产物。3.1.3杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作一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 methyl 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 (3x100 ml). The combined organic phases were washed by brine, dried over MgSO 4, filtered and concentrated. The residue was purified by column chromatography to afford the product (, yield50%).3.1.4杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作二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 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 (3x300 mL). The combined organic phases were washed by brine, dried over MgSO 4, filtered and concentrated. The residue was purified by column chromatography to afford the product (15 g, yield 50%).Note: Pd(OAc)2的质量有时是实验成败的关键，i+ COOH3A 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 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 215-216.5 °C.3.1.6非共轭双键Heck反应示例ArX +WEt (3 eq.)OEt1.3 mol% Pd(OAc)22 eq. Bu4NOAc1.5 eq. K2CO31 eq. K2CO3, DMF, 90oC2. 2N HCl, rt, 10 minAr'*' CHOTypical procedure for the preparation of cinnamaldehyde:To a stirred solution of -iodoanisole (0.117 g, 0.5 mmol) in 2.0 mL of DMF were added acrolein diethyl acetal (0.229 mL, 1.5 mmol), «Bu4NOAc (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. 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 Na 2SO4 and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 35 g; -hexane/ethylacetate 90/10 v/v) to give 0.071 g (88%) of -methoxycinnamaldehyde.3.2不对称分子间Heck反应1992年，Tamio Hayashi等报道了手性钯催化的环状烯烃的不对称Heck芳基化反应。ArOTf +a: Ar = Ph (>96% ee)1b: Ar = p-ClC6H4 (>96% ee)c: Ar = p-MeOC H (87% ee)6 41d: Ar = 2-naphthyl (>96% ee)Pd(OAc)2-2(A)-BINAPrbase, benzene, 40 C 、O ArTamio Hayashi, Pure & Appl. Chem., 1992, 64(3), 421-427碱对芳基花产物的对应选择性有一定的影响。 例如，用高位阻的强碱性1，8-双若用2，6-二甲基毗啶作碱（N,N-二甲氨基）萘时，其1a的对应选择性超过96%ee。时，1a的对应选择性为69%ee。ArOTf +.Pd(OAc)2-2(R)-BINAP> O+ base, - base-HOTfin benzene1a: Ar = Ph (>96% ee)1b: Ar = Q-ClC6H4 (>96% ee)1c: Ar = m-ClCH (>96% ee) 641d: Ar = O-CIC6H4 (92% ee)1e: Ar = p-AcC6H4 (>96% ee)1f: Ar = q-NcC&H4 (>96% ee)1g: Ar = p-MeOCH (87% ee)641h: Ar = 2-naphthyl (>96% ee)3.3 非常用离去基团的 Heck 反应(Irina P. Beletskaya Chem. Rev. 2000, 100, 3009-3066)Beller等人报道了重氮盐参与的Heck反应不需要膦催化剂和胺，条件温和，是很COOMe实用的芳基化反应。COOMe5% Pd/CMeOH, 40-60 °C ArArN2BF4 +jCOOMeBeller, M.; Kuehlein, K. Synlet t1995, 441碘盐参与的Heck反应条件也比较温和，用水作溶剂反应较快，适用于一些惧怕激 烈反应条件的底物。对于二芳基碘盐的Heck反应，一般常温下得到一取代的产物，回 流条件下得到二取代产物。忠，OH + p bF4削。啊或札P/OH24CH3CN/H2O(5:1), rtKang, S.-K. J. Org. Chem. 1996, 61, 2604酰氯参与的Heck反应一般在非极性溶剂中使用弱碱即可，无需膦催化剂，而且所需钯催化剂用量极少(0.005 mol%)。OClBrNaOAc, DMF, 100-130°C=YYSpencer, A. J. Organomet. Chem. 1984, 265, 323将酸酐应用于Heck反应时20世纪末才发现的，它的优点在于不需要任何碱的存 在。R PdCl2, NaB2=/NMP,100 C ArGuertler, C. Chem. Eur. J. 1999, 5, 31070.01 eq Pd-catOMeO2R3.3.1重氮盐参与的Heck反应示例Solvent 40-60°CTable 1. Heck Reaction of p-Methoxyphenyldiazonium Tereafluoroborate With Acrylic Acid 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 weight 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 in40 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°C 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 and the crude product is further purified by crystallized or chromatography on silca.3.3.2酰氯参与的Heck反应示例产 CO2Et2+HNMe2+HNHMe2 Cl+ COPreparation of (E)-ethyl 4-bromocinnamic acid (II)To p-xylene (200 mL) were added palladium acetate (0.02244 g, 0.1 mmol), I (21.95 g, 0.1 mol), ethyl acrylate (10.83 mL, 0.1 mol) and Mbenzyldimethylamine (15.06 mL, 0.1 mol). The mixture was stirred for 1 h at 130°C. At room temperature it was filtered and the precipitate was washed with toluene(50 mL). This gave nearly pureMbenzyldimethylammonium chloride (15.74 g, 92%) from which the base can be readily recovered. The combined filtrates were extracted with 2 N hydrochloric acid (50 mL), 2 N aqueous sodium hydroxide (50 mL) and water (50 mL). After drying with MgSO 4 (10 g) for 15 min, the solvents were removed on the rotary evaporator and the crude product was fractionally distilled in vacuum (130-135°C/0.2 mmHg). Yield 20.1 g (79%). Colourless liquid. Anal. Found: C, 52.07; H, 4.50; Br, 31.01. C 11H11BrO2 calcd.: C, 51.79; H, 4.35; Br, 31.32%.The End