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 (3)1.1 Suzuki反应的通式 (3)1.2 Suzuki反应的机理 (3)1.3 Suzuki反应的特点及研究方向 (4)2 有机硼试剂的合成 (4)2.1 通过金属有机试剂制备单取代芳基硼酸 (4)2.1.1 通过Grinard试剂制备单取代芳基硼酸示例 (4)2.1.2 通过有机锂试剂制备单取代芳基硼酸示例 (5)2.2 通过二硼烷频哪酯制备芳基硼酸酯 (6)2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一） (9)2.2.2 通过二硼烷频哪酯制备芳基硼酸酯示例（二） (10)2.2.3 通过芳基硼酸转化为芳基硼酸酯 (10)2.3 烯基硼酸酯的制备 (10)2.4 烷基硼酸酯的制备 (10)3 催化剂的制备 (11)3.1 Pd(PPh3)4的制备 (11)3.2 Pd(PPh3)2Cl2的制备 (12)3.3 Pd(dppf)Cl2的制备 (12)4Suzuki偶联的应用 (12)4.1 普通的芳卤和芳基硼酸的Suzuki偶联 (13)4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例 (14)4.2 大位阻芳基硼酸参与Suzuki偶联反应 (14)4.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应 (15)4.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联 (16)4.3.2 带着酯基底物的Suzuki偶联反应示例（一） (16)4.3.3 带着酯基底物的Suzuki偶联反应示例（二） (17)4.4 杂环芳基硼酸参与Suzuki偶联反应 (17)4.5烷基硼酸参与Suzuki偶联反应 (18)4.6烯基硼酸参与Suzuki偶联反应 (19)4.7 Triflate参与Suzuki偶联反应 (19)4.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例 (20)4.7.2 芳基的Triflate与芳基硼酸偶联示例 (20)4.8 芳基氯参与Suzuki偶联反应 (21)4.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一） (21)4.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二） (22)4.9 镍催化体系用于Suzuki偶联反应 (22)4.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例 (22)4.10 其他方法 (23)4.10.1 直接Pd/C用于Suzuki偶联反应示例 (23)4.10.2 直接Pd(OAc)2用于Suzuki偶联反应示例 (23)1 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。
B(OH)2+3 mol% [Pd(PPh )]aq Na 2CO 3benzene or toluene refluxSuzuki 反应的通式R1BY 2R2X[Pd]R 1R 2+baseBY 2 = B(OR)2, 9-BBN, B(CHCH 3CH(CH 3)2)X = I, Br, Cl, OSO 2(C n F 2n+1), n = 0,1,4R 1 = aryl, alkenyl, alkylR 2 = aryl, alkenyl, alkynyl, benzyl, allyl, alkyl[Pd] = Pd(PPh 3)4, Pd(dppf)Cl 2base = Na 2CO 3, NaOCH 2CH 3, TIOH, N(CH 2CH 3)3, K 3PO 41.2 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（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1: ArMgX+B(OMe)3ArB(OH)2H3O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2。
RLi+B(OPr i)3ArB(OPr i)22.1.1 通过Grinard试剂制备单取代芳基硼酸示例FFF BrMg B(OMe)3Et2O THFFF B(OH)2A 500-mL, three-necked, round-bottomed flask containing magnesium turnings (1.94 g, 80 1Gerrard, 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.; Sokolik, R. A. Methods of Elemento-Organic Chemistry;North-Holland: m sterdam, 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 307 and ref 12.2Brown, 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.; Rangaishenvi, M. V. Tetrahedron Lett. 1990, 49, 7113, 7115.mmol) is equipped with a rubber septum, a 20-mL pressure-equalizing dropping funnel fitted with a rubber septum, a Teflon-coated magnetic 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 filled 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). The 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 mL, 14.5 g, 140 mmol). The mixture is cooled to 0°C, 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 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. The resulting white solid is dissolved in a minimal amount of hot (65°C) 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. 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3I TMS(HO)2BTMS1. nBuLi, THF-78o C, 15min2. B(OMe)3-78o C-25o C, 30min3. H+/HCl3Chem. 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) 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, dried (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X X(RO)2B-B(OR)2Pd(dppf)Cl2KOAcDMSO, 80℃B(OR)2X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。