HIGH TEMPERATURE HECK COUPLING

经典化学合成反应标准操作药明康德新药开发有限公司化学合成部编写前言有机合成研究人员在做化学反应经常碰到常规的反应手边没有现成的标准操作步骤而要去查文献，在试同一类反应时，为了寻找各种反应条件方法也得去查资料。

为了提高大家的工作效率，因此化学合成部需要一份《经典合成反应标准操作》。

在这份材料中，我们精选药物化学中各类经典的合成反应，每类反应有什么方法，并通过实际经验对每类反应的各种条件进行点评，供大家在摸索合成条件时进行比较。

同时每种反应的标准操作，均可作为模板套用于书写客户的final report，这样可以大大节省研究人员书写final report的时间，也相应减少在报告中的文法错误。

另外本版是初版，在今后的工作中我们将根据需要修订这份材料。

药明康德新药开发有限公司化学合成部2005-6-28目录1.胺的合成a)还原胺化b)直接烷基化c)腈的还原d)酰胺的还原e)硝基的还原f)叠氮的还原g)Hoffman降解h)羧酸通过Cris 重排2.羧酸衍生物的合成a)酰胺化的反应b)酯化反应c)腈转化为酯和酰胺d)钯催化的插羰反应e)酯交换为酰氨3.羧酸的合成a)醇氧化b)酯水解c)酰胺的水解d)腈的水解e)有机金属试剂的羰基化反应f)芳香甲基的氧化4.醛酮的合成a)Weinreb 酰胺合成醛酮b)醇氧化c)酯的直接还原d)有机金属试剂对腈加成合成酮5.脂肪卤代物的合成a)醇转化为脂肪溴代物通过PBr3 转化通过PPh3 与CBr4 转化HBr直接交换通过相应的氯代物或磺酸酯与LiBr交换、b)醇转化为脂肪氯代物通过SOCl2转化通过PPh3 与CCl4 转化HCl直接交换c)醇转化为脂肪碘代物通过PPh3 与I2 转化通过相应的氯代物或磺酸酯与NaI交换6.芳香卤代物的合成a)Sandermyyer 重氮化卤代b)直接卤代c)杂环的酚羟基或醚的卤代7.醇的合成a)羧酸或酯的还原b)醛酮的还原c)卤代烃的水解d)吡啶的氧化转位8.酚的合成a)Sandermayer 重氮化反应b)醚的水解c)Bayer-vigerlar 氧化d)硼酸的氧化9.腈的合成a)磺酸酯或卤代烃的取代b)酰胺的脱水c)芳卤代烃的氰基取代10.硝化反应11.醚的合成a)芳香醚的合成酚与烷基卤代烃的直接烷基化Mitsunobu 芳香醚化Buckwald芳香醚化b)脂肪醚的合成醇的醚化12.脲的合成a)胺与异腈酸酯的反应b)用三光气合成脲c)羰基二咪唑（CDI）合成脲d)对硝基苯酚碳酰胺合成脲13.烯烃的合成a)Wittig 反应b)羟基的消除c)Wittig-Horner 反应合成α,β-不饱和酯14.磺酸及磺酰氯的合成a)氯磺化反应合成磺酰氯b)从硫醇合成磺酰氯c)磺化反应15.氨基酸的合成a)Streck 反应合成b)手性氨基酸的合成16.偶联反应a)Suzuki Couplingb)Buckwald 芳胺化，芳酰胺化、c)Heck 反应17.Mitsunobu 反应a)醇的反转b)胺的取代18.脱羟基反应19.酮还原为亚甲基20.氨的保护及脱保护策略a)用碳酰胺作保护基b)苄基保护21.醇的保护及脱保护策略a)用硅醚进行保护b)其他醚类保护22.羧基的保护格氏反应---------------------------------------------------------------------------------------------------------1还原胺化---------------------------------------------------------------------------------------------------------2卤化反应---------------------------------------------------------------------------------------------------------2 Suzuki coupling-------------------------------------------------------------------------------------------------2磺化反应---------------------------------------------------------------------------------------------------------3酯化反应---------------------------------------------------------------------------------------------------------3水解反应---------------------------------------------------------------------------------------------------------3硝化反应---------------------------------------------------------------------------------------------------------4 n-BuLi------------------------------------------------------------------------------------------------------------4 LiAlH4还原-----------------------------------------------------------------------------------------------------4 POCl3的杂环氯代----------------------------------------------------------------------------------------------5 NaH---------------------------------------------------------------------------------------------------------------5 NBS---------------------------------------------------------------------------------------------------------------5m-CPBA ----------------------------------------------------------------------------------------------------------6EDC ---------------------------------------------------------------------------------------------------------------6用三光气成脲---------------------------------------------------------------------------------------------------7芳卤用n-BuLi 处理后与Weinreb 酰胺成酮-----------------------------------------------------------------7Boc 上保护OHH 2NHO OOOOOO OHN HO OHO O ABTo a solution of A (2.72 g, 13.9 mmol) and tetramethylammonium hydroxide pentahydrate (5.62 g, 31.0 mmol) in acetonitrile (270 mL) was added di-tert-butyldicarbonate (3.79 g; 17.4 mmol) and the resulting solution was allowed to stir 18 h at rt and concentrated. The residue was partitioned between Et2O/H2O; the phases were separated and the aqueous phase extracted twice more with Et2O. The aqueous phase was brought to pH 4 with solid citric acid and extracted with CHCl3 (3.x.100 mL). The organic extracts were combined, dried (Na2SO4) and concentrated to afford 2.58 g (63 percent) B as a white foam.ReturnBoc 脱保护OON HOOOOH 2NTert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8 g, 89 mmol) in dichloromethane (10 ml) was cooled to 0 deg C and stirred as a mixture of trifluoroacetic acid: dichloromethane (1:1, 40 ml) was added dropwise. The mixture was allowed to warm to rt, stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3*20 ml) and aqueous sodium hydroxide (10percent, 3*20 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphenoxy)ethylamine (13 g, 88percent yield) as a light yellow solid.Return格氏反应NCNNOA stirred mixture of magnesium turnings (23.6 g, 0.98 mol) and Et2O (200 mL) under nitrogen is treated with a crystal of iodine and about 5percent of a solution of bromoethane (56.3 ml, 0.75 mol) in Et2O (375 mL). When the reaction starts, the remainder of the bromoethane solution is added, dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring is continued for 1 hour. To this solution of ethylmagnesium bromide was slowly added a solution of 4-cyanopyridine (39 g, 0.375 mol) in Et2O (750 ml). The reaction mixture was warmed at reflux for 12 hours, treated with concentrated H2SO4 (125 ml)/H2O (125 ml), and then washed three times with Et2O (250 ml). The aqueous portion was made basic (PH 9) with 15percent NaOH solution and extracted five times with 250 ml portions of Et2O. The combined Et2O extracts were dried (MgSO4), and the solvent was removed under reduced pressure to afford a brown oil (48.4 g, 95percent).Return还原胺化OHO H 2N+HON HA solution of 2-amino-4-ethylphenol (1.00 g. 7.28 mmol), 2-naphthaldehyde (1.13 g, 7.28 mmol), andp-toluenesulfonic acid (0.05 g) in methanol (50 ML) was stirred at room temp for 24 h. To the resultant solution, sodium borohydride (0.82 g, 22 mmol) was added in small portions. After addition was completed, the mixture was stirred at room temperature for 30 min and concentrated under vacuum. The residue was then subjected to column chromatography on silica gel eluted with 10percent ethyl acetate in hexane and followed by recrystallization (aqueous methanol) yielded 450 mg (22percent) of analytically pure product.Return卤化反应O2N O2NBrTo a stirred solution of 8-methyl-1-nitro-naphthalene (10.6g, 56.32 mmol) and iron (III) chloride (0.45 g, 2.77 mmo) in CCl4 (150 ml) heated to 60°C was added dropwise (3.0 ml, 58.23 mmol) of bromine. After one hour, the reaction mixture was poured into saturated NaHCO3 solution, and the layers were separated. The aqueous layer was re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was recrystallized from ethanol and the mother liquors were concentrated and then flash chromatographed on silica, eluding hexanes:ethyl acetate (12: 1).ReturnSuzuki couplingBrBOO NH+NH To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mnmol) and3-bromobenzene (0.87 ml, 8.3 mmol) in THF (28 ml) were added palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 ml of water).The system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70 °Coil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluding with hexanes: EtOAc 9:1 to give 1.38 g (78%yield) of 4-phenyl-1H-indole as a colorless liquid.Return磺化反应NOFFFNOFFFSOClOChlorosulfonic acid (4.66g, 40 mmol) is added dropwise to a cold (0°C) solution of2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (2.9g, 8 mmol) in chloroform (800 ml). The resulting solution is stirred at 0°C for 30 minutes. The cold bath is then removed and the solution is stirred at room temperature for 1 hour then cautiously poured into ice water. The organic layer is separated, dried over magnesium sulfate and concentrated to afford the title compound. The crude product is purified by column chromatography eluted with 10% acetic ether in petroleum ether (2.36 g, 81% yield).Return酯化反应HOHO O HOO OA mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 ml), and concentrate H2SO4(2 ml) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO3 (2*), brine, dried over MgSO4, and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%yield).Return水解反应OO OHOA solution of 1-Methyl-naphthalene-2-carboxylic acid methyl ester (7.20g, 35mmol) and 2N sodium hydroxide (35ml) in tetrahydrofuran (130ml) was stirred under reflux for 18 hours. The mixture was neutralised using 2N hydrochloric acid, and extracted with dichloromethane (3x). The combined organic solutions were dried (MgSO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gelusing an elution gradient of dichloromethane: methanol (100:0 to 97:3) to afford the title compound as a solid (3.11g, 47.8%yield).Return硝化反应NO 2To a cold (0°C) suspension of 1-methylnaphthalene (5 g, 35.2 mmol) in HNO3 was added H2SO4 (5 ml) dropwise. After stirring the reaction for one hour, the solution was diluted with ethyl acetate and washed with water (3*), aqueous saturated NaHCO3 (2*) and brine, dried over MgSO4, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate: hexane (5: 95) and recrystallized from methanol to give yellow needles (0.22g, 33% yield).Returnn-BuLiEtOCF 3O CF 3O NCTo a dry three-necked round-bottomed flask with an addition funnel and at -78°C under inert atmosphere was charged with anhydrous THF (500 ml). A solution of n-butyllithium (2.5 M in hexane, 88ml, 220 mmol) was added dropwise followed by addition of a solution of acetonitrile (10.43 ml, 200 mmol) in anhydrous THF (100 ml). The internal temperature was maintained below -70°C during the entire addition process. After 2 hr at -78°C a solution of Trifluoro-acetic acid ethyl ester (14.2 g, 100 mmol) in anhydrous THF (30 ml) was added dropwise and the mixture was stirred for 1.5 hr. To the mixture was added acetic anhydride to quench the reaction. The reaction mixture was allowed to warm up to rt. A precipitate was filtered and the filtrate was concentrated to give a brown oil, which was used in the next step without purification.ReturnLiAlH4还原HOHO O OHOHOA solution of 2,3-naphthalenedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 ml, warmed to 50° to maintain solution) is added dropwise over 15 minutes to a 1.15 M lithium aluminum hydride solution in THF (45 ml, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully with THF-water, then 2N hydrochloric acid (40 ml) is added, and the resulting mixture is extracted 3 times with ether. The combined ether extracts are washed with water (2 times), with saturated sodium bicarbonate solution (1 time), with water, and are dried (sodium sulfate), filtered, and concentrated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g, 67.3%yield) as a light tan crystalline material.ReturnPOCl3的杂环氯代NN HOOHN NClClTo a suspension of 2,4-dihydroxy-5,6-dimethylpyrimidine (6.2 g, 0.044 mol) in POCl3 (25 ml) was slowly added N,N-dimethylaniline (6.18 ml, 0.049 mol). The mixture was then refluxed at 125 °C for 3 hours. After this time, the starting material completely dissolved indicating that the reaction was completed.The reaction mixture was cooled and then poured slowly onto ice to quench the POCl3(caution[exothermic]). A precipitate formed, which was filtered and washed with ice-cold water. The precipitate was dried under high vacuum overnight to yield 2,4-dichloro-5,6-dimethyl-pyrimidine (7.2 g, 0.041 mol, 92%yield) as a yellow solid.ReturnNaHHSH 2N Cl +SNH 2Sodium hydride (50% in mineral oil, 5.5 g, 0.11 mol) was added portionwise at 0 °C under a nitrogen atmosphere to a solution of 2-aminobenzenethiol (12 ml, 0.1 mol) in DMF (120 ml). After 0.5 h, benzyl chloride (11.5 ml, 0.1 mol) in DMF (80 ml) was added in 0.5 h. The solution was stirred for 3 h while the temperature was allowed to rise to rt, then it was poured into ice/water (1000 g). The precipitate was filtered, dissolved in ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and evaporated. The solid obtained was ground in pentane (19.3 g, 90% yield).ReturnNBSNN FCl ClNBSN N FCl ClBrA mixture of 2,4-Dichloro-6-ethyl-5-fluoro-pyrimidine (27.46 g ， 0.14mol), AIBN (1.32 g) and n-bromosuccinimide (27.02 g ， 0.152mol) in CH2Cl2 (170 ml) was refluxed under a nitrogen atmosphere for 36 h. Then washed by water, the aqueous was extracted by CH2Cl2. The combined organic layer was washed by saturated Na2S2O3 and brine, dried over Na2SO4, and evaporated to give a white solid which was purified by column chromatography eluted with 50% acetic ether in petroleum ether (34 g, 88.6% yield).Return氢化反应O ONH OONH2Cl ClA mixture of ethyl 3-(N-benzylamino)-3-methylbutyrate hydrochloride (25g, 0.1 mol) and 10percent Pd-C (2g) in 250 ml of dried alcohol was hydrogenated under 55 psi H2 for four days. The reaction medium was then filtered and evaporated under reduced pressure to provide an amber oil which gradually crystallized upon standing (18 g, 100% yield).Returnm-CPBAS NH2SNH2OA solution of 85% m-chloroperoxybenzoic acid (19 g, 94 mmol) in CH2Cl2 (350 ml)was added at –5 –0 °C to a solution of 2-Benzylsulfanyl-phenylamine (19 g, 88 mmol) in CH2Cl2 (400 ml). The mixture was allowed to warm to rt in 3 h, then it was washed with a 5% Na2S2O3 solution, 10% NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and evaporated. The solid was ground in pentane (19 g, 95% yield).ReturnEDCNH2OHNOO+HOHOHNOOTo a 0°C mixture of Boc-L-tyrosine (2.04 g, 7.26 mmol) and amylamine (0.63 gl, 7.26 mmol) in methylene chloride (30 ml) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (1.53 g, 9.9 mmol). Thewhite mixture is stirred at 0°C for 5 min and at room temp for 23 hrs. The resulting solution is diluted with methylene chloride (30 ml) and washed successively with 0.5 M HCl (40 ml), water (20 ml) and sat aq sodium bicarbonate (25 ml). The organic phase is dried over magnesium sulfate and concentrated to a foam (1.84 g, 72.4%yield), sufficiently pure to carry into the next step. An analytical sample is obtained by HPLC.Return三光气成脲NH 2ONO 2Si O Cl Cl ClO O Cl Cl ClO 2NHN H NO OHOHNO 2+To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) in toluene (10 ml) triethylamine (0.13 ml, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. The reaction mixture was stirred at 70 °C for 2 hours, then cooled to room temperature. Then more 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70 °C for 48 hours then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane: ethyl acetate, 10:1) gave 1,3-Bis-(2-hydroxy-4-nitro-phenyl)-urea (130 mg, 31%yield).Return芳卤用n-BuLi处理后与Weinreb酰胺成酮N FFFFNOO+FFFO NFTo a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at –78°C under argon was added n-butyllithium (54.0 ml, 2.5M in hexane, 0.135 mole), followed after 5 min by dropwise a solution of 2-fluoro-4-methylpyridine (10 g, 0.090 mole) in THF (20 ml). After stirring for 15 min at –78°C, a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 ml) was added dropwise. After stirring for more 5 min, the reaction was allowed to warm to 0°C and quenched by pouring into water (400 ml) and ethyl acetate (400 ml). The layers were separated, and the aqueous layer washed with ethyl acetate (200 ml). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20percent ethyl acetate in hexane to give 21.6 g of 2-(2-Fluoro-pyridin-4-yl)-1-(3-trifluoromethyl-phenyl)-ethanone (84.8%yield).Return。

2003 年 , 法国学者 Levillain 等报道[17] , 他们用 ( R) 222氨基丁醇与二硫代异丙酸甲酯经缩合反应后 得到具有手性碳原子的噻唑啉 ,用卤代烷将其季铵 化 ,再与 HPF6 或 HBF4 共热使 HX 挥发除去 ,即得到 手性离子液体. 同年 ,我国北大的学者 Ma Hong2yang 等也发表论文报道[18] ,从 L2( - ) 2薄荷醇出发 ,经 3 步反应 ,制得两种 N ,N′二取代咪唑六氟磷酸盐 ,并 测定了它们的熔点和比旋光度. 这些结果似乎表明 , 离子液体用于不对称合成的研究已经展开.
摘要
离子液体是一类性能优异 、用途广泛 、安全环保的溶剂. 本文简要介绍了离子液体的组成 、制备 、性质和应用等 方面的研究进展 .
关键词 :离子液体 , 合成 , 性质 , 绿色溶剂. 中图分类号 :O 64511
离子液体 (ionic liquids) 就是在室温 (或稍高于室温 的温度) 下呈液态的离子体系 ,或者说 ,离子液体是 仅由离子所组成的液体. 在组成上 ,它与我们概念中 的“盐”相近 ,而其熔点通常又低于室温 ,所以 ,也有 人把离子液体叫做“室温熔融盐”( room2temperature molten salts) .
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首都师范大学学报 (自然科学版)
2005 年
转蒸发器上蒸去丙酮后 ,在真空 ( < 50mTorr) 120 ℃ 下干燥 ,即可得到离子液体 [ emim ]BF4 . 这样就可以 避免使用昂贵的银盐.
另外 ,利用离子液体的不挥发性 ,将 N2取代的 杂环卤盐与 HBF4 、HPF6 共热 ,使生成的 HX 逸出 ,也 是制备酸根离子为 BP24 或 PF26 的离子液体的一种可 选择的方法[17 ,18] .

能够影响偶联反应，这是因为大多这类反应都是通过不饱和金属络合物发生反应，而这些络合物都不满足18共价电子的稳定结构。

[编辑]偶联反应类型常见的偶联反应包括：反应名称发现年代反应物A反应物B类型催化剂备注武兹反应（Wurtz reaction）1855 R-X sp³R-X sp³自身以Na消除反应物的卤原子格拉泽偶联反应（Glaser coupling）1869 RC≡CH sp RC≡CH sp自身Cu氧气作为H受体乌尔曼反应（Ullmann reaction）1901 Ar-X sp²Ar-X sp²自身Cu 高温冈伯格-巴克曼反应1924 Ar-H sp²Ar-N2X sp²自身需碱参与Cadiot-Chodkiewicz偶联反应1957 RC≡CH sp RC≡CX sp交叉Cu需碱参与Castro-Stephens偶联反应1963 RC≡CH sp Ar-X sp²交叉Cu吉尔曼试剂偶联反应（Gilman reagent coupling）1967 R2CuLi R-X交叉Cassar反应1970 烯烃sp²R-X sp³交叉Pd需碱参与熊田偶联反应（Kumada coupling）1972 Ar-MgBrsp²,sp³Ar-X sp²交叉PdorNi赫克反应（Heck reaction）1972 烯烃sp²R-X sp²交叉Pd需碱参与薗头偶联反应（Sonogashira coupling）1975 RC≡CH sp R-Xsp³sp²交叉PdandCu需碱参与根岸偶联反应（Negishicoupling ）1977 R-Zn-X sp³,sp², sp R-Xsp³ sp² 交叉 PdorNi施蒂勒反应（Stille coupling ） 1978 R-SnR 3sp³,sp², spR-X sp³ sp² 交叉 Pd铃木反应（Suzuki reaction ） 1979 R-B(OR)2 sp² R-X sp³ sp² 交叉 Pd需碱参与 Hiyama 偶联反应1988 R-SiR 3sp² R-Xsp³ sp² 交叉 Pd需碱参与 Buchwald –Hartwig 偶联反应1994R 2N-RSnR 3sp R-Xsp² 交叉Pd N-C偶联反应福山偶联反应（Fukuyama coupling ） 1998 RCO(SEt) sp 2 R-Zn-I sp 3 交叉 Pd。

钯及其配合物催化剂在Heck反应中的应用陈德勇【摘要】钯及其配合物催化剂在有机合成中具有广泛的应用.主要综述钯催化Heck反应近年来的最新进展,重点介绍了各种配体在钯催化Heck反应中的所起的作用.【期刊名称】《凯里学院学报》【年(卷),期】2011(029)003【总页数】5页(P47-51)【关键词】钯;配合物;催化剂;Heck反应【作者】陈德勇【作者单位】榕江县第一中学,贵州,榕江,557200【正文语种】中文钯催化的偶合反应是现代有机合成中行之有效的构建C-C键的方法,而 Heck反应是烯烃芳基化、链烯化非常重要的有机反应,主要用于各种取代烯烃等不饱和化合物的合成.在近20年来,该反应被广泛应用于天然产物、药物分子以及新型材料的合成,为低碳经济的发展提供了广阔的应用前景[1-2].本文拟从 Heck反应的发现、机理以及在有机合成中的应用实例进行总结.20世纪70年代初期,由 Mirozoki与 Heck[3]相继发现了卤代芳烃与不饱和烃在钯催化下可以构建C-C键,产物以反式为主.后经 Heck深入的研究,发现该反应可以广泛应用于天然产物、生物活性物质、精细化学品及其中间体的合成,这就是典型的 Heck反应(见图 1).底物大多为卤代芳烃(反应活性为 ArI＞ArBr＞ArCl)与含有α-吸电子基取代端烯反应,生成以反式为主的芳香烯烃,常用Pd(0),Pd(II)或Pd配合物为催化剂.合成化学发展至今非常快,特别是有机化合成,现代有机合成具有自己的特点,即高选择性(化学选择性、区域选择性和立体选择性)、高产率、反应条件温和、操作简便和对环境友好.而 Heck反应可以实现一步合成C-C键,在温和条件下获得高选择性的化合物,因而发展成为当今构建高选择性C-C键的重要反应之一[4].Heck反应机理就目前研究表明是一个循环催化过程,分为5步:(a)预活化,(b)氧化加成,(c)配位迁移插入,(d)β-H消除,(e)催化剂再生.Pd(0),Pd(II)或Pd配合物的催化活性在于Pd(0)的稳定性.对于含有配位原子(如N,P)配体催化剂体系中,一般认为配位原子与Pd(0)作用生成配合物起到稳定Pd(0)的作用.在无配位原子催化剂体系中,是由亲核试剂或其它试剂或离子参与完成预活化过程[5-8].Pd(0)对C-X键的氧化加成非常重要,C-X键极性影响加成的进行,因而卤代烃反应活性顺序为RI＞ROTf＞RBr＞RCl.新C-C键形成于配位与迁移插入步骤,并决定产物构型,通过缚酸剂和 HX 作用,回到Pd(0)状态进入新一轮循环.在1998年,Shaw[9]小组报道反应机理为Pd(Ⅱ)-Pd(Ⅳ)机理,认为环钯化合物无需预处理,通过解聚变为单体进入催化循环.事过3年,由Sundermann[10]小组通过计算2种机理中间态能量,结果显示,Heck反应机理趋向于 Pd(0)-Pd(Ⅱ)反应机理.如图2所示.该反应机理表明:卤代烃R-X与 Pd(0)发生氧化加成生成中间体4,C=C与4中的Pd配位后,发生C=C双键对C-Pd键的順式共平面插入反应,形成一个C-C单键和一个新的C-Pd键而获得中间体5,然后发生顺式共平面β-H消除得目标化合物反式取代烯烃,同时产生钯氢化合物,在碱的存在下在还原为Pd(0)[11].针对钯催化 Heck反应,由于钯催化的活性中心钯必需是零价的钯,而零价的钯在反应中非常容易团聚而生成钯黑失去活性,从而使反应无法继续进行,所以在使用钯作为 Heck反应的催化剂时一般需要加入配体来稳定和活化催化剂.因而研究者近年来的研究主要集中在如何发现新的更有利于反应发生的配体的研究上,图3是已被应用于偶联反应中的钯络合物.在无配体条件下,同样可以实现 Pd催化的Heck反应,效果不错,因而吸引了一些研究者的兴趣.2000年,Reetz[7]小组报道了纳米颗粒级的 Pd在无配体条件下催化的Heck反应,为 Pd催化剂提供新思维.2003年,由 Yao[12]等报道了无配体条件下采用Pd(OAc)2催化溴苯的反应,但该反应体系只对芳基溴化物有较好的效果.2006年,由周浩[13]等人以氟离子插层的水滑石LDH-F为载体,制备了新型 Pd/LDH-F 催化剂,并用其催化溴代芳烃的 Heck反应,发现在无配体和恒量钯存在下即可显示出很高的催化活性和选择性;反应后的催化剂经简单处理可循环4次使用其催化活性基本不变.最近由陈为[14]等人报道了以Pd(OAc)2为催化剂,Ag2CO3为添加剂,在甲苯或苯中回流12 h,实现了各种芳基卤代烃与丙烯酸酯、苯乙烯等烯基化合物的 Heck反应.该方法无需配体参与、反应条件温和、操作简单及产物收率高.很早以来,偶联反应中配体被大量的使用,尤其是不对称合成反应中通常利用手性配体诱导底物实现不对称合成.近年来,更多新型高效配体被发现能够有效的促进卤代芳烃的 Heck反应.一般是通过配体侧链上的配位原子(N,P,S,O)与钯进行配位所得,具有较好的稳定性和重复使用性.1995年,Heramann[15]等首次将环钯催化剂6与螯合物7应用于催化氯代芳烃的Heck反应,发现对于溴苯和被活化的氯苯几乎完全转化,并且有很好的选择性.事隔2年,Milstein[16]等设计了新的钯配合物(PCP型螯合物)8-10,并将其应用于溴苯和碘苯的 Heck反应中,取得了较好的结果.随后,由Jensen[17]等进一步修饰和改进该类螯合物结构,制备出新螯合物11,11可以催化大部分氯代芳烃,如含有位阻和富电子基团的底物.但是难以合成,并不能回收.2001年,Gruber[18]等报道了非膦催化体系PdCl2(SEt2)2/nBu4Br,发现可以催化氯代芳烃和苯乙烯的 Heck偶联反应,产率达到91%.2000年,Reddy[19]等首次使用含有膦氢的钯配合物12—14催化溴苯与碘苯的 Heck反应,发现效果很好.2年后,由Loch[20]等合成含有三配位的卡宾型钯配合物15-17,比较它们的催化活性,发现分子外侧具有烷基长链的16效果最好,对于被活化的对氯苯甲醛几乎完全转化.2004年,由Yao[21]等在PCP型螯合物基础上,合成新的钯配合物18-20,由于硒的存在,不仅提高催化能力,而且抑制其不被空气所氧化,从而提高稳定性.2004年,由Fan[22]等合成了类似于 PCP型配合物PNP 型催化剂21,在110℃时能有效的催化溴代芳烃的 Heck反应.同年,Kovala-Demertzi[23]等也报道了含硫配合物22,不但同样能够有效的催化溴代芳烃的Heck反应,而且在空气中反应时依然能够显示出高活性的催化能力.Pd催化的 Heck反应是构建C-C键的重要反应之一.上面是针对以膦化合物为配体来调整钯催化剂的催化活性和选择性.由于多数Pd-膦配合物对空气稳定性差、易氧化;在溶液中易解离出膦配体而降低催化剂活性.研究者不得不寻找新的、更稳定的配体来替代膦配体.1991年,Arduengo[24]小组成功分离出游离的N-杂环卡宾(NHC)后,其合成方法及催化反应性能倍受合成工作者的高度关注.NHC具有如下特点:(1)NHC是富电子体,与有机膦配体相似;(2)NHC的供电子能力比膦配体强,可与钯配位形成稳定性更高的 Pd-氮配合物,可以催化Pd-膦配合物催化的反应,显示出更优越的催化性能;(3)合成条件温和,操作简单.下面介绍 Pd-氮配合物催化剂的一些应用实例.2007年,Fiddy[25]等通过改变两个配位原子间的距离,在咪唑的N1上接吡啶基,N3上接大位阻取代基,合成一系列 Pd-氮配合物23,并应用于Heck反应,对碘代苯、溴代苯与丙烯酸酯的反应活性优于 Pd-膦配合物的催化效能.2005年,Frey[26]等报道了 Pd配合物24、25催化芳基溴及乙酰基芳基氯与苯乙烯的 Heck反应,其催化性能比不含NHC的好.2007年,Taige[27]等合成了4种侧链上连有不同取代基的双Pd-NHC化合物26,并研究了他们的催化性能,发现苯基对位取代基对双Pd-N HC化合物26的结构影响甚微,但是环上电子云密度及催化性能影响较为明显.在催化 Heck反应时,发现26a—26d的催化活性优于26e和26f.双大环的 Pd-NHC配合物27,在催化芳基卤代物与苯乙烯的 Heck反应时,发现对溴代烃的偶合产物产率远远优于氯代烃[28].总之,NHC化合物的催化研究刚刚开始,与Pd-膦配合物的催化相互补充,具有潜在的应用价值.这基于咪唑盐的NHC类Pd-氮配合物的配体比膦配体易固载化,适于多相催化反应,从而克服均相催化的不足.相信在不久将实现Pd-NHC化合物在工业催化、材料合成等领域的应用[29].2007年,徐启杰[30]等利用廉价易得的腐植酸作为载体,通过简单的方法制得了腐植酸负载Pd/Ni双金属催化剂.能够很好的催化溴苯及其取代基溴苯与丙烯酸或苯乙烯的 Heck反应,所得产物产率均在85%以上.反应条件温和、催化剂用量少、反应时间短,在催化溴苯与丙烯酸或苯乙烯的反应中,催化剂不可重复使用.2009年,唐中民[31]等利用 MCM-41分子筛固载腈Pd(0)合成了新的MCM.(CH2)3CN﹒Pd(0,Ⅱ)配合物催化剂.该催化剂具有良好的催化性能和稳定性,并应用于碘代芳烃与共轭烯烃的Heck偶联反应,反应条件为:以DMF-Et3N为溶剂、70℃、0～7 h下,高产率、高选择性地合成了一系列E式取代产物,产物分离收率达到84%以上.为高产率高选择性地合成取代的E式1,2-二苯乙烯和E式肉桂酸等提供了一种新方法.Heck反应通常是指过渡金属钯催化的芳基卤与烯烃之间构建碳碳键的偶联反应.Heck反应的底物来源广泛,反应步骤简单,其生成的产物是许多天然产物中的基本骨架.因此,Heck反应现已广泛用于合成自然界中的复杂天然产物.由于过渡金属钯催化中最常用的配体是膦配体,而膦配体又存在着诸多难以克服的缺点如价格昂贵、遇水或空气容易分解以及众所周知的高毒性等,所以,膦配体的应用有一定的局限性.目前人们对 Heck反应的研究主要集中在寻找高效、低毒、稳定的配体以及寻找价格更便宜的其它过渡金属如Cu和Ni等来代替传统的钯催化.近年来,许多钯配合物催化剂相继被合成并应用于 Heck反应,这些报道不但加深了人们对 Heck 反应催化原理的理解,同时也为化学工作者提供了大量新的构建C-C单键的方法,这些方法大多具备原子经济性,操作简单,环境友好,催化剂往往也易于制备和储藏,目前已有被应用于药物以及天然产物的合成中,具有广阔的应用前景.此外,钯催化的应用,也赋予了许多经典反应新的内容,加深了人们的认识,克服了一些以往的缺点和局限性,拓展了它们的应用范围。