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Pd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 NaHSO(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%.

(0)

相关推荐

  • Adv. Synth. Catal.:利用钯催化偕二溴烯烃和P(O)H化合物的多米诺环化/膦化反应实现含膦杂环的合成

    杂环化合物广泛存在于众多天然产物.农用化学品.药物.功能材料和染料中.在这其中,吲哚.苯并呋喃和苯并噻吩等杂芳环及其衍生物具有独特的生物和药理活性,例如Psoralen, Benzbromarone, ...

  • 实用|氧化还原成烯偶联人名反应

    引言 数据图表是进行知识归纳整理最有效的方法之一. 常用.实用的数据图表,可以给人们学习.工作.生活带来极大的便利. 化学科学,不得不提到的表格是俄国科学家门捷列夫(Dmitri Mendeleev) ...

  • Corey-Winter烯烃化

    定义: 通过环1,1-硫代羰基二咪唑(TCDI)和三甲氧基膦立体定向将二醇转化为相应的烯烃的反应,被称为Corey-Winter烯烃化,又叫Corey-Winter还原消除,或Corey-Winter ...

  • 实用|缩合成环重排人名反应

    引言 数据图表是进行知识归纳整理最有效的方法之一. 常用.实用的数据图表,可以给人们学习.工作.生活带来极大的便利. 化学科学,不得不提到的表格是俄国科学家门捷列夫(Dmitri Mendeleev) ...

  • 亚硝酸钠和醋酐氧化示例

    一个较实用的合成醛的方法,反应一般在室温下进行,反应时间较短,可氧化大部分伯醇.烯丙醇和苄醇,而且产率较高,副反应较少.一般仲醇很难反应,可能会生成亚硝酸酯. 反应示例 A typical proce ...

  • 重氮盐参与的Heck 反应

    芳基重氮盐可以发生的反应最常见的就是Sandmeyer反应可以制备卤代芳烃,芳基酚或芳基腈,另外就是Balz-Schiemann反应制备芳基氟化物,偶氮偶合反应制备偶氮二芳基类化合物.1995年Bel ...

  • Meerwein芳基化反应

    1939年,H. Meerwein团队对芳基重氮化合物与α,β-不饱和羰基化合物进行偶联的反应进行了系统的研究.其中发现,香豆素和对氯苯基重氮氯盐在催化量的氯化铜催化下得到了中等产率的 3-(对氯苯基 ...

  • 【有机】JACS:有机催化[12+2]环加成构建Cycl[3.2.2]azine

    通常情况下,复杂的分子结构往往需要较长的合成路线来保证转化的选择性,而近年来有机催化的高阶环加成反应通过一步反应就可形成复杂的环状结构.现代催化技术提供了传统Diels-Alder反应难以得到的产物, ...

  • 【有机】Nat. Commun.:卤代烷烃在区域选择性还原烯烃加氢烷基化反应中的作用

    导读: 近日,南京林业大学博士生陈先枭在该校饶卫东教授和新加坡国立大学许民瑜(Ming Joo Koh)教授指导下,在Nat. Commun.发表论文,报道了通过将镍催化剂与化学计量的还原剂相结合,从 ...

  • 【有机】JACS:铑氢催化实现碳碳双键的高选择性氢化

    不饱和有机化合物的催化氢化在学术界和工业界都具有广泛的应用,特别是在药物制备.香料等精细化学品的合成等领域.其中,α,β-不饱和羰基化合物的1,4-还原尤其引起了人们的关注.除氢气作为氢源之外,硅氢. ...