Suzuki反应-20060226

1、经典合成反应标准操作Suzuki反应 药明康德新药开发有限公司经典化学合成反应标准操作Suzuki 反应编者：刘德军、武伟药明康德新药开发有限公司化学合成部目 录1 前言31.1 Suzuki反应的通式31.2 Suzuki反应的机理31.3 Suzuki反应的特点及研究方向42 有机硼试剂的合成42.1 通过金属有机试剂制备单取代芳基硼酸42.1.1 通过Grinard试剂制备单取代芳基硼酸示例42.1.2 通过有机锂试剂制备单取代芳基硼酸示例52.2 通过二硼烷频哪酯制备芳基硼酸酯62.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一）92.2.2 通过二硼烷频哪酯制备芳基硼酸酯示例（二）1

2、02.2.3 通过芳基硼酸转化为芳基硼酸酯102.3 烯基硼酸酯的制备102.4 烷基硼酸酯的制备103 催化剂的制备113.1 Pd(PPh3)4的制备113.2 Pd(PPh3)2Cl2的制备123.3 Pd(dppf)Cl2的制备124Suzuki偶联的应用124.1 普通的芳卤和芳基硼酸的Suzuki偶联134.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例144.2 大位阻芳基硼酸参与Suzuki偶联反应144.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应154.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联164.3.2 带

3、着酯基底物的Suzuki偶联反应示例（一）164.3.3 带着酯基底物的Suzuki偶联反应示例（二）174.4 杂环芳基硼酸参与Suzuki偶联反应174.5烷基硼酸参与Suzuki偶联反应184.6烯基硼酸参与Suzuki偶联反应194.7 Triflate参与Suzuki偶联反应194.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例204.7.2 芳基的Triflate与芳基硼酸偶联示例204.8 芳基氯参与Suzuki偶联反应214.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一）214.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二）224.9 镍催化体系用于Suzuki偶

4、联反应224.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例224.10 其他方法234.10.1 直接Pd/C用于 Suzuki偶联反应示例234.10.2 直接Pd(OAc)2用于 Suzuki偶联反应示例231 前言1.1 Suzuki反应的通式在钯催化下，有机硼化合物与有机卤素化合物进行偶联反应，这就提供了一类常用和有效的合成碳-碳键化合物的方法，我们称之为Suzuki 偶联反应，或Suzuki-Miyaura 偶联反应。 Suzuki反应的通式1.2 Suzuki反应的机理Suzuki 偶联反应的催化循环过程通常认为先是Pd(0)与卤代芳烃发生氧

5、化-加成反应生成Pd(II) 的络合物 1，然后与活化的硼酸发生金属转移反应生成Pd(II)）的络合物 2，最后进行还原-消除而生成产物和Pd(0)。 1.3 Suzuki反应的特点及研究方向这类偶联反应有一些突出的优点，比如：1.反应对水不敏感； 2. 可允许多种活性官能团存在；3. 可以进行通常的区域和立体选择性的反应，尤其是，这类反应的无机副产物是无毒的并且易于除去，这就使得其不仅适用于实验室而且可以用于工业化生产。其缺点是氯代物（特别是空间位阻大的氯代物）及一些杂环硼酸反应难以进行。目前，Suzuki 偶联反应的研究主要在以下几个方面：（1）合成并筛选能够在温和的条件下高效催化卤代芳烃

6、（特别是氯代芳烃）的配体；（2）多相催化体系的Suzuki偶联反应研究；（3）应用于Suzuki 偶联反应的新合成方法研究。2 有机硼试剂的合成2.1 通过金属有机试剂制备单取代芳基硼酸经典合成单取代芳基硼酸(酯)的方法是用格氏试剂或锂试剂和硼酸酯反应来制备 Gerrard, W. The Chemistry ofBoron; Academic: New York, 1961. Muetterties, E. L. The Chemistry of Boron and its Compounds; Wiley: New York, 1967. Nesmeyanov, A. N.; Sokoli

7、k, R. A. Methods of Elemento-Organic Chemistry; North-Holland: msterdam, 1967; Vol. 1. Koster, R. Houben-Wey Methoden der Organischen Chemie; Georg Thieme: Verlag Stuttgart, 1984. Matteson, D. S. The Chemistry of the Metal-Carbon Bond;Hartley, F., Patai, S., Eds.; Wiley: New York, 1987; Vol. 4, p 30

8、7 and ref 12.:用这种经典方法的缺点是单取代芳基硼酸酯有进一步生成二取代硼酸，甚至三烷基硼的可能，因此反应须在低温下进行。解决这个问题的一个有效的办法是使用硼酸三异丙酯和有机锂试剂反应, 可以避免二烷(芳)基硼烷和三烷(芳)基硼烷的产生。反应完后通常加入稀盐酸酸化直接高收率地得到芳基硼酸酯 Brown, H. C.; Cole, T. E. Organometallics 1983,2, 1316. Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988,29,2631. Brown, H. C.; Rangais

9、henvi, M. V. Tetrahedron Lett. 1990, 49, 7113, 7115.。2.1.1 通过Grinard试剂制备单取代芳基硼酸示例A 500-mL, three-necked, round-bottomed flask containing magnesium turnings (1.94 g, 80 mmol) is equipped with a rubber septum, a 20-mL pressure-equalizing dropping funnel fitted with a rubber septum, a Teflon-coated mag

10、netic stirring bar, and a reflux condenser fitted with an argon inlet adapter. The system is flame-dried and flushed with argon. Anhydrous ether (200 mL) is introduced to cover the magnesium, a crystal of iodine is added, and the mixture is heated to reflux in an oil bath. The dropping funnel is fil

11、led with 1-bromo-3,4,5-trifluorobenzene (8.36 mL, 14.8 g, 70.0 mmol) and ca. 1 mL is added to the boiling reaction mixture. After reaction has commenced, the oil bath is removed, and the remainder of the aryl bromide is added slowly at a rate sufficient to maintain reflux (addition time ca. 1 hr). T

12、he resulting mixture is stirred for an additional 2 hr. During this period, a flame-dried, 500-mL, single-necked, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar, a rubber septum, and an argon inlet is charged with dry tetrahydrofuran (THF, 50 mL) and trimethyl borate (15.7

13、mL, 14.5 g, 140 mmol). The mixture is cooled to 0C, and the ether solution of (3,4,5-trifluorophenyl)magnesium bromide prepared above is introduced in one portion via a double-ended needle. The reaction mixture is allowed to warm to room temperature, stirred for 1 hr, and then treated with 200 mL of

14、 saturated ammonium chloride solution. The organic layer is separated and the aqueous layer is extracted with three 100-mL portions of ethyl acetate. The combined organic layers are washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

15、 The resulting white solid is dissolved in a minimal amount of hot (65C) ethyl acetate, allowed to cool to room temperature, and then 600 mL of hexane is added. The resulting solution is allowed to stand overnight and then filtered to afford pure (3,4,5-trifluorophenyl)boronic acid as white crystals

16、. Further recrystallization of the mother liquor 3-4 times provides a total of 6.3 g (51%) of (3,4,5-trifluorophenyl)boronic acid.2.1.2 通过有机锂试剂制备单取代芳基硼酸示例 Chem. Eur. J. 2003, 9, 4430-4441nBuLi (1.6_ in hexane, 1 mL, 1.6 mmol) at - 78 under nitrogen was added to a solution of 4-(trimethylsilylethynyl

17、) iodobenzene (0.3 g, 1.13 mmol) in THF (5 mL). After stirring for 15 min at - 78, trimethylborate (0.2 mL, 1.6 mmol) was added in one portion. The mixture was warmed to 25 , stirred for 30 min, and quenched with dilute HCl solution. The mixture was extracted with EtOAc (20 mL), washed with water, d

18、ried (MgSO4) and evaporated to obtain the crude 4-(trimethylsilylethynyl) phenylboronic acid that was used without further purification.2.2 通过二硼烷频哪酯制备芳基硼酸酯对于分子中带有酯基、氰基、硝基、羰基等官能团的芳香卤代物来说, 无法通过有机金属试剂来制备相应的芳基硼酸。 1995年由Ishiyama Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.率先取得了突破:

19、通过二硼烷频哪酯和芳基卤发生偶联反应制备相应的芳基硼酸酯 (yield: 60-98%)。这个方法还有一个突出的优点就是还可以原位制备硼酸酯, 然后“一锅法”和芳基卤反应用于芳基-芳基偶联反应。在极性溶剂里此偶联反应的产率可以得到很大的提高：DMSO DMF dioxane toluene。经过验证，KOAc是应用于这个反应最合适的碱，其他的如K3PO4或K2CO3这些碱性略强的碱会进一步使原料芳基卤发生自偶联反应的结果。对于制备溴代物和碘代物相应的芳基硼酸酯，Pd(dppf)Cl2一般可以得到很好的结果，又由于其具有易于反应的后处理的优点，因此是公司目前最常用的一类催化剂。对于氯代物，200

20、1年Ishiyama经过研究发现在 Pd(dba)2/2.4PCy3(3-6mol %) 的催化下此类反应可以接近当量的进行 Tatsuo Ishiyama, Tetrahedron 57 (2001) 9813-9816，下表是研究过程中对配体的遴选的情况：Table 1. Effect of ligands in the reaction of bis(pinacolato)diboron (2, 1.1 mmol) with 4-chlorobenzaldehyde (1.0 mmol) in dioxane (6 ml) at 80C for 16 in the presence of

21、 KOAc (1.5 mmol), Pd(dba)2 (3 mol%), and a phosphine ligand (3.3-7.2 mol%)EntryLigandLigand (equiv.)aYield (%)b1None12PPh32.4193P(o-MeC6H4)32.4364P(p-MeOC6H4)32.4445dppfc1.118641.178752.468861.110971.17110PCy32.49411P(t-Bu)32.458a Equivalents to palladium metal.b GC yields based on 4-chlorobenzaldeh

22、yde.c 1,1-Bis(diphenylphosphino)ferrocene.如Table 2所示，对一些有代表性的芳基氯进行硼酸酯化反应。对于含有吸电子集团的芳基氯，例如NO2、CN、CHO和CO2Me（Entry 1,3,5 and 6），反应进行的很快。而对于含有给电子集团(Entry 8-13)或有位阻影响的集团(Entry 2, 4)的芳基氯，反应就明显缓慢下来，需要更长的时间和更多的催化剂来完成。例外的是，2-氯吡啶(Entry 15)不能得到目标产物。对这种氯原子紧邻芳环杂原子的芳基氯进行反应的过程中，产生的硼酸或硼酸酯实在是太敏感了，很容易就转变为杂原子芳环，如吡啶。Ta

23、ble 2. Synthesis of pinacol arylboronatesEntryChloroareneMol%aTime (h)Yield (%)b14-O2NC6H4Cl348822-O2NC6H4Cl3487234-NCC6H4Cl349842-NCC6H4Cl3487254-OHCC6H4Cl369464-MeO2CC6H4Cl36877C6H5Cl6489184-MeC6H4Cl6489292-MeC6H4Cl34886104-MeOC6H4Cl64878113-MeOC6H4Cl64892122-MeOC6H4Cl34870134-Me2NC6H4Cl64873142-C

24、hloronaphthalene34877152-Chloropyridine3480163-Chloropyridine3488217348731834872a Mol% of catalyst.b GC yields based on chloroarenes.对于一些富电子的芳基氯化物和碘化物，用Pd(dppf)Cl2进行硼酸酯化的收率较低，而用Pd(dba)2/2.4PCy3(3-6mol %)在dioxone中会得到较好的结果，如下表所示：EDGX=Catalyst/solventTime/hYield%MeOIPdCl2(dppf)/DMSO282BrPdCl2(dppf)/DMS

25、O2469BrPd (dba) 2-PCy3/dioxane781OTfPdCl2(dppf)-dppf/dioxane1393OTfPd (dba) 2-PCy3/dioxane283Me2NIPdCl2(dppf)/DMSO690BrPdCl2(dppf)/DMSO2423BrPd (dba) 2-PCy3/dioxane681 2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一）A flask charged with palladium catalyst (0.03 mmol), KOAc (294 mg, 3.0 mmol), and diboron (279 mg, 1.1 mmo

26、l) was flushed with nitrogen. DMSO (6 mL) and haloarene (1.0 mmol) were then added. After being stirred at 80 for an appropriate period, the product was extracted with benzene, washed with water, and dried over anhydrous magnesium sulfate. Kugelrohr distillation in vacuo gave the arylboronates. 2.2.

27、2 通过二硼烷频哪酯制备芳基硼酸酯示例（二）2.2.3 通过芳基硼酸转化为芳基硼酸酯A solution of 4-(dihydroxyboryl)benzoic acid (1.66 g, 10 mmol) and pinacol (12 mmol) in toluene (70 m) was refluxed in a Dean-Stark apparatus for 16 hours and concentrated. The concentrate was triturated with diethyl ether and filtered to provide the desired

28、 product of sufficient purity for subsequent use.2.3 烯基硼酸酯的制备 Brown, H. C.; Imai, T. Organometallics 1984, 3, 13921395.2.4 烷基硼酸酯的制备 Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458460.2-3-(tert-Butyldimethylsiloxy)-1,2-syn-dideuteriopropyl-2-cyclohexen-1-one (syn-7). Propene cis-2 (150 mg,

29、 0.86 mmol) was added to a solution of 9-BBN (126 mg, 1.03 mmol) in THF (15 mL) at 0 C. The reaction mixture was heated to reflux for 12 h. The mixture was cooled to 25 C, and 2-iodo-2-cyclohexene-1-one (229 mg, 1.03 mmol), Pd(dppf)Cl2 (14 mg, 0.017 mmol), and NaOH (0.6 mL, 3 M, aqueous) were added

30、sequentially. The mixture was again brought to reflux where it remained for 2 h. The reaction mixture was partitioned between NaCl (75 mL, saturated aqueous) and Et2O (50 mL). The aqueous phase was separated and washed with 2 _ 25 mL of Et2O. The combined organic layers were dried over Na2SO4, filte

31、red, and reduced in vacuo. Purification by flash chromatography (10:90 EtOAc:hexane) yielded pure product as a colorless oil (119 mg, 51%).3 催化剂的制备3.1 Pd(PPh3)4的制备 A mixture of palladium dichloride (17.72 g., 0.10 mole), triphenylphosphine (131 g, 0.50 mole), and 1200 ml of dimethyl sulfoxide is pla

32、ced in a single-necked, 2L, round-bottomed flask equipped with a magnetic stirring bar and a dual-outlet adapter. A rubber septum and a vacuum-nitrogen system are connected to the outlets, The system is then placed under nitrogen with provision made for pressure relief through a mercury bubbler. The

33、 yellow mixture is heated by means of an oil bath with stirring until complete solution occurs (ca. 140). The bath is then taken away, and the solution is rapidly stirred for approximately 15 minutes. Hydrazine hydrate (20 g, 0.40 mole) is then rapidly added over approximately 1 minute from a hypode

34、rmic syringe. A vigorous reaction takes place with evolution of nitrogen. The dark solution is then immediately cooled with a water bath; crystallization begins to occur at ca. 125. At this point the mixture is allowed to cool without external cooling. After the mixture has reached room temperature

35、it is filtered under nitrogen on a coarse, sintered-glass funnel. The solid is washed successively with two 50 ml. portions of ethanol and two 50 ml portions of ether. The product is dried by passing a slow stream of nitrogen through the funnel overnight. The resulting yellow crystalline product wei

36、ghs 103.5-108.5 g. (90-94% yield). A melting point determination on a sample in a sealed capillary tube under nitrogen gave a decomposition point of 116 (uncorrected). This compares with a similar determination (115) performed on the product prepared by the method of Malatesta and Angoletta. Propert

37、ies: The Pd(PPh3)4 complex obtained by this procedure is a yellow, crystalline material possessing moderate solubilities in benzene (50 g/L), methylene chloride, and chloroform. The compound is less soluble in acetone, tetrahydrofuran and acetonitrile. Saturated hydrocarbon solvents give no evidence

38、 of solution. Although the complex may be handled in air, it is best stored under nitrogen to ensure its purity.3.2 Pd(PPh3)2Cl2的制备将PdCl2 (50 g, 0.284 mol)和PPh3 (162.5 g, 0.62 mol) 加入苯腈（150 mL）中，氮气置换三次，升温到200，反应30 分钟，降温至室温析出晶体，滤出固体，用乙醚洗涤，抽干，得到产品（362 g, 95.8 %）。3.3 Pd(dppf)Cl2的制备To absolute acetonitr

39、ile (1950 mL) degassed via three vacuum/nitrogen ingress cycle was added dichloropalladium (13 g, 73 mmol), the mixture was refluxed at 90100 C overnight. The reactant was concentrated to obtain Pd(CH3CN)2Cl2 as orange solid. To a suspension of Pd(CH3CN)2Cl2 (19 g, 73 mmol) in benzene (680 mL) was a

40、dded a solution of dppf (40.6 g, 73 mmol) in benzene (680 mL), the mixture was stirred at rt overnight, the reddish brown precipitate formed was collected by filtration, washed with benzene, and dried in vacuo to give Pd(dppf)2Cl2 (48 g) in over 90% yield. This is pure enough for the next step, the

41、complex can be recrystallized from chloroform/benzene.4 Suzuki偶联的应用在整个suzuki-coupling反应循环中，Pd(0)与卤代芳烃发生氧化-加成反应生成Pd(II) 的络合物这一步被认为是起决定作用的步骤。底物卤代芳烃中离去集团的相对活性有如下特征：I - Otf - Br - Cl -。芳基和烯基上若带有集团，则吸电子集团对氧化-加成的促进作用要比给电子集团强。在Pd(II)）的络合物的还原-消除得到偶联产品的步骤中，相对的速率为：arylaryl alkylaryl n-propyln-propyl ethylethy

42、l methylmethyl应用于suzuki反应的催化剂最经典的是Pd(PPh3)4，其它的有PdCl2、PdCl2(dppf)、Pd(OAc)2、Pd(PPh3)2Cl2和NiCl2(dppf) 等等，它们分别具有一些如后处理容易、空气敏感度低等的特点，在具体的反应上有成熟的应用。有些反应还需要另外一些高催化活性的配体的参与，它们具有的共性就是电负性较强和空间位阻大。这是因为电负性较强的配体是有利于氧化加成反应；空间位阻大的配体有利于还原消除。开发高效价廉的新催化剂和配体是一个研究的方向。4.1 普通的芳卤和芳基硼酸的Suzuki偶联这一类反应是我们最常碰到的，所用的方法即为Suzuki偶

43、联反应的普通操作： 在水的存在下，加入催化剂、碱和有机溶剂，加热回流一段合理的时间完成反应，但反应体系必须全程严格控制在无氧的环境下。通常如果反应可行的话，这种方法所得的产率也是较高的。碱的话多用K2CO3，也有K3PO4、 Na2CO3、CsF、Cs2CO3、t-Bu-Na等等,一般不用NaHCO3。碱的强度对大位阻的2,4,6-三甲基硼酸的偶联反应的影响次序是: Ba(OH)2 NaOH K3PO4 Na2CO3 NaHCO3。但是, 用弱碱往往比用强碱反应干净一些溶剂体系一般用toluene/ EtOH / H2O, 也有CH3CN / H2O或dioxane / H2O。Table 3

44、是Suzuki反应的常用条件:Table 3 The general conditions for Suzuki coupling a) Gronowitz, S.; Bobosik, V.; Lawitz, K. Chem. Scr. 1984,23, 120. b) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A,; Snieckus, V. J . Org. Chem. 1991,56, 3763.EntrySolventsCatalystBaseTemperature1dioxanePd(PPh3)4

45、K2CO31202DMFPd(PPh3)4K3PO4803DME / H2OPd(PPh3)4Na2CO3refluxed4Toluene / H2O, MeOHPd(PPh3)4Na2CO3refluxed5DMF / H2OPd(dppf)Cl2Na2CO31206MeCN / H2OPd(PPh3)4Na2CO3refluxed4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例 Patent; Takeda Chemical Industries, Ltd.; Publ.: US6518257 B1 (2003/02/11)Under an arg

46、on atmosphere, p-dibromobenzene (9.99 g), 4-methoxyphenylboronic acid (2.03 g) and tetrakistriphenylphosphine palladium (497 mg) were dissolved in dimethoxyethane (20 ml). A 2M aqueous sodium carbonate solution (20 ml) was added and the mixture was heated under reflux for 14 h. The reaction mixture

47、was cooled to room temperature and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and insoluble materials were filtered off. The solvent was evaporated and the obtained solid was washed with hexane to give the title compound (2.09 g) as

48、a colorless solid.4.2 大位阻芳基硼酸参与Suzuki偶联反应芳基硼酸的立体位阻对Suzuki偶联反应的影响比芳基卤的立体位阻对Suzuki偶联反应的影响大得多。当芳基硼酸的邻位是二取代物时, 反应的速率很慢, 收率很低。加入强碱水溶液如NaOH或Ba(OH)2, 以苯和DME为溶剂对反应有显著的加速作用 a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207. b) Kelly, T. R.; Garcia, A.; Lang, F.; Walsh, J. J.; Bhaskar, K.V.; Boyd, M.

49、 R.; Gotz, R.; Keller, P. A,; Walter, R.; Bringmann, G. Tetrahedron Lett. 1994,35, 7621. c) Guillier, F.; Nivoliers, F.; Godard, A,; Marsais, F.; Queguiner, G. Tetrahedron Lett. 1994, 35, 6489.。碱的强度对2,4,6-三甲基硼酸的偶联反应的影响次序是: Ba(OH)2 NaOH K3PO4 Na2CO3 NaHCO3。但是, 用弱碱往往比用强碱反应干净一些 Watanabe, T.; Miyaura, N

50、.; Suzuki, A. Synlett 1992, 207.。有时候可以将大位阻芳基硼酸转化为硼酸酯，可以取得满意的结果 J. Organomet. Chem. 2002, 653, 269.。4.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应2-醛基苯硼酸和2-碘甲苯在Na2CO3水溶液和DME中80反应, 目标化合物的收率只有39%. 提高收率的一个方法是: 使用相应的芳基硼酸酯代替芳基硼酸, 以无水K3PO4为碱, 用DMF作溶剂, 收率可以提高到89%6. 如果芳基硼酸或芳卤本身带有其它对水敏感的集团，如易水解的酯基（尤其是甲酯，乙酯活性还低些）、氰基等等，这时也可以应用

51、这种方法，实验证明在无水的情况下，即使碱不溶解，很多的底物也可以进行Suzuki偶联反应。相应的芳基硼酸酯的制备方法可参考前述有关章节。如果底物既带着酯基又只能在有水存在下才能反应的，怎么办？ 方法之一：加入痕量的水, 如果底物本身含有甲酯就不能在toluene/EtOH/H2O里反应了，因为会发生酯交换反应，但只要把其中的EtOH换成MeOH即可解决这个问题。方法之二：先得到羧酸产物然后再酯化。例如 4.3.3所示操作:4.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联To a solution of 3.862 g of I and 3.401 g of II in 80 mL of

52、 dioxane and 20 mL of water was added 2.245 g of K2CO3 followed by 0.328 g of (Ph3P)4Pd under N2 with stirring. The mixture was refluxed for several hours until the material was disaappeared. The reaction mixture was cooled to room temperature. The dioxane was removed by rotary evaporation. The resi

53、due was poured into water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and the solvent was removed by rotary evaporation. The product was isolated by flash chromatography on silica gel using 10:90 EtOAc-hexanes as eluant. The product was a clear, colorless oil. 4.3.2 带

54、着酯基底物的Suzuki偶联反应示例（一） Patent; Augeri, David J.; Publ.: US2002/55631 A1 (2002/05/09)A mixture of methyl 4-bromobenzoate (21.5 g, 100 mmol), 4-fluorophenylboronic acid (14.7 g, 105 mmol), Pd(dppf)Cl2, CH2Cl2(1.48 g, 2.0 mmol), and 2M Na2CO3(100 ML) in toluene (200 ML) and was heated to reflux, stirred

55、 for 10 hours, diluted with ethyl acetate (200 ML), washed with water (100 ML) and brine (50 ML), dried (MgSO4), filtered, and concentrated.The concentrate was recrystallized from ethyl acetate/hexanes to provide the desired product. The mother liquor was concentrated and purified by flash column ch

56、romatography on silica gel with 10percent ethyl acetate/hexanes to provide additional product. 4.3.3 带着酯基底物的Suzuki偶联反应示例（二） http:/www.rhodium.ws/chemistry/lysergic.hendrickson.htmlInto 500 ml anhydrous toluene in a 1 liter round bottom flask equipped with stirring bar was bubbled in a stream of argon via a needle for 30 min. Pd(PPh3)4 (0.878g, 0.75 mmol) and 3-chloro-pyridine-2,5-dica