Heck 反应应用一览
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。
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。
Mori和 Ban于1977年首次报道了分子内的Heck反应：
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
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。
2.1.1分子内Heck反应化生成环外双键示例
Astirred solution of 1 (98 mg, 0.19 mmol), triethylmine (0.32 mL, 2.3mmol) and catalytic tetrakis(triphenylphosphine)palladium(0) (ca. 5 mg, 4 μmol)in 2.4 mL of acetonitrile was heated at 80 ℃in a sealed tube under an argon atmosphere for 10 h. The reaction mixtureturned dark orange after ca. 10 min, and the catalyst plated out on the wallsof the tube as a shiny layer of palladium metal upon completion of thereaction. The reaction mixture was cooled to room temperature; the reaction wasquenched with aqueous NaHCO3(15 mL), and the mixture was extractedwith EtOAc (4×10 mL). The organicextracts were washed with aqueous NaHSO3 (1×15 mL), water (1×15 mL), and brine (1×15 mL) and dried over MgSO4.Filtration, concentration, and purification of the orange residue by flashcolumn chromatography (45:55 Et2O/hexanes) gave 66 mg (90%) of 19 asa 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Overman首先报道不对称Heck反应。
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。
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。
2.2.1分子内不对称Heck反应示例
A mixture of Pd2(dba)3·CHCl3 (360 mg,0.347 mol), (s)-BINAP (504 mg, 0.809 mol), and N,N-dimethylacetamide (DMA, 21mL) was stirred at room temperature for 65 min. To the resulting orangesolution 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 aqueousNaHCO3 (100 mL) and extracted with ether (3 × 150 mL). The combinedorganic extracts were washed with brine (100 mL), dried (MgSO4), andconcentrated, and the residue was purified by sgc (9:1 → 1:1 hexane-EtOAc) to giveoxindole enoxysilane compound 2 (1.29 g, 94%) as a 98:2 mixture of geometric isomers: [α]25D–81o (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。
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。
2.2.1 Heck反应用于合成大环多烯示例
A solution ofvinyl 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. Theresulting suspension was stirred at room temperature for 15 min and then heatedat 65 ℃ in a sealed tube for 12 h. A blacksuspension resulted after 10-20 min at 65 ℃.After GC analysis of a filtered aliquot showed that the reaction had notproceeded 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, andthe black suspension was stirred in a sealed tube at 65 ℃for an additional 6 h. The suspension was then cooled to room temperature andfiltered through a plug of silica gel (1.5 cm×12 cm, EtOAc), and the filtratewas concentrated to give the crude Heck product as a yellow oil.
This samplewas dissolved in THF (4 mL), and TBAF (1.0 M solution in THF, 2.0 mL) was added. The resulting solutionwas maintained at room temperature for 20 h and quenched with saturated aqueousNH4Cl (20 mL). The resulting mixture was extracted with CH2Cl2(3×20 mL), the combinedorganic layers were dried (NaSO4), filtered and concentrated, andthe residue was purified by flash chromatography (4:1 hexanes-EtOAc) to provide370 mg (90%) of tricyclic allylic alcohol 2 as a pale yellow oil: Rf=0.25(5:1hexanes-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β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β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α,β-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腈，而丙烯腈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。
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。
目前，我们应用该反应最多的是芳基卤代物和α,β-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
Amixture 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 ina heavy-walled Pyrex tube at 100.deg. C. for 6 h.The cooled reaction mixturewas diluted with DCM (60 ML) and distilled water (30 ML).The organic layer waswashed with distilled water (3*25 ML).The aqueous layer was extracted with DCM(25 ML).The combined organic layers were dried over sodium sulfate andconcentrated under reduced pressure to give a pale yellow solid.Purification byrecrystallization with EtOAc and hexanes gave an off-white crystalline solid (1.82 g; 85percent):
3.1.2 不饱和酮的Heck反应标准操作
A mixture of 4-bromotoluene (10.0 mmol), Cyclohex-2-enone (10mmol), 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) in DMF (30 mL) was heated under N2at 100 oC for 6-12 h. Thereaction mixture was cooled, diluted with 50 mL of water and extracted withether (2 x 50 mL). The combined organic portion was washed with brine solution,dried over anhydrous magnesium sulfate and finally filtered. Evaporatation ofthe volatiles under reduced pressure purification with column chromatography togive 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), tetrabutylammoniumiodide (30 g, 82mmol) and K2CO3(28 g, 205 mmol) in N,N-dimethylformide (130 mL) wasdegassed 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; theaqueous layer was extracted with Et2O (3×100 ml). The combinedorganic phases were washed by brine, dried over MgSO4, filtered andconcentrated.The residue was purified by column chromatography to afford the product(, yield~50%).
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/nitrogeningress cycle, and then added methyl acrylate (46.0mL, 511mmol), the mixturewas stirred at 100 oC overnight. To the mixture was added water; theaqueous layer was extracted with Et2O (3×300 mL). The combinedorganic phases were washed by brine, dried over MgSO4, filtered andconcentrated. 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，
3.1.5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
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 heatedin a steam bath for 1 hour. After the reaction mixture had been cooled, it wasdiluted with 250 mL 10% aq. HCl. The solid formed was collected by filtrationand re-crystallized from ethanol to give compound 3 (1.86 g, yield 82%), mp 215-216.5℃.
3.1.6非共轭双键Heck反应示例
Typical procedure for thepreparation of cinnamaldehyde:
To a stirred solution of p-iodoanisole(0.117 g, 0.5 mmol) in 2.0 mLof 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 stirredfor 1.5 h at 90oC. After cooling, 2 N HCl was slowly addedand the reaction mixture was stirred ar room temperature for 10 min. Then, itwas diluted with ether and washed with water. The organic layer was dried overNa2SO4 and concentrated under reduced pressure. Theresidue was purified by chromatography (silica gel, 35 g; n-hexane/ethylacetate 90/10 v/v) to give 0.071 g (88%) of p-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。
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（N,N-二甲氨基）萘时，其1a的对应选择性超过96%ee。若用2，6-二甲基吡啶作碱时，1a的对应选择性为69%ee。
3.3 非常用离去基团的Heck反应（Irina P. BeletskayaChem. 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，是很实用的芳基化反应。
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。
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%）。
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。
3.3.1重氮盐参与的Heck反应示例
Generalprocedure for the synthesis of cinnamic acid esters:
30 mmol of corresponding diazonium salt and 60 mmol of acrylic acid esterare suspended in 40 mL of the solvent. Subsequently, 0.6 mmol of palladium on activatedcharcoal (5% weight) is added at 0°C.Then the reaction mixture is heated to 60°C in the course of 1 hour and stirred for12 hours at this temperature. After cooling to room temperature, the catalystis filtered off and washed with the solvent. The solvent is evaporated in vacuoand the crude product is further purified by crystallized or chromatography onsilca.
3.3.2酰氯参与的Heck反应示例
Preparationof (E)-ethyl 4-bromocinnamic acid (II)
Top-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 N-benzyldimethylamine (15.06 mL, 0.1 mol). The mixture wasstirred for 1 h at 130°C.At room temperature it was filtered and the precipitate was washed with toluene(50 mL). This gave nearly pure N-benzyldimethylammonium chloride (15.74 g, 92%) from which the base can bereadily recovered. The combined filtrates were extracted with 2 N hydrochloricacid (50 mL), 2 N aqueous sodium hydroxide (50 mL) and water (50 mL). Afterdrying with MgSO4 (10 g)for 15 min, the solvents were removed on the rotary evaporator and the crudeproduct 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. C11H11BrO2 calcd.:C, 51.79; H, 4.35; Br, 31.32%.