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1、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
2、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
3、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
4、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
5、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)2Br ZZ + 3 mol% Pd(PPh3)4 aq Na2CO3 benzene or toluene reflux Suzuki 反应的通式 R1BY 2R 2 X Pd R 1 R2 + base BY2 = B(OR) 2, 9-BBN, B(CHCH3CH(CH3)2) X = I, Br, Cl, OSO 2(CnF2n+1), n = 0,1,4 R 1 = aryl, alkenyl, alkyl R 2 = aryl, alkenyl,
6、 alkynyl, benzyl, allyl, alkyl Pd = Pd(PPh 3)4, Pd(dppf)Cl2 base = Na 2CO3, NaOCH2CH3, TIOH, N(CH2CH3)3, K3PO4 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
7、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
8、剂或锂试剂和硼酸酯反应来制备 1: ArMgX+B(OMe)3ArB(OH) 2 H3O 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) 2 HCl 2.1.1 通过 Grinard 试剂制备单取代芳基硼酸示例 F F F Br MgB(OMe)3 Et2OTHF F F F B(OH)2 A 5
9、00-mL, three-necked, round-bottomed flask containing magnesium turnings (1.94 g, 80 1 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.; Sokolik, R. A. Methods of Elemento-Organic Chemist
10、ry; 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 307 and ref 12. 2 Brown, H. C.; Cole, T. E. Or
11、ganometallics 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-coate
12、d 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 i
13、s 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 h
14、r). 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、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
16、 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 pre
17、ssure. 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 c
18、rystals. 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 3 I TMS (HO)2B TMS1. nBuLi, THF -78 o C, 15min 2. B(OMe)3 -78 oC-25oC, 30min 3. H +/HCl 3 Chem. Eur. J. 2003, 9, 4430-4441 nBuLi (1.6_ in
19、 hexane, 1 mL, 1.6 mmol) at - 78under 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 que
20、nched 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) 2 Pd(dppf)Cl2 KOAc DMSO, 80
21、B(OR)2 X 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 4率先取得了突破 : 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：DMSODMF 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
22、发生自偶联反应的结果。 4 Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. 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， 2001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 5，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 o
23、f 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 KOAc (1.5 mmol), Pd(dba)2 (3 mol%), and a phosphine ligand (3.3-7.2 mol%) Entry Ligand Ligand (equiv.) a Yield (%)b 1 None 1 2 PPh32.4 19 3 P(o-MeC6H4)32.4 36 4 P(p-MeOC6H4)
24、32.4 44 5 dppf c 1.1 18 6 4 1.1 78 7 5 2.4 68 8 6 1.1 10 9 7 1.1 71 10 PCy32.4 94 11 P(t-Bu)32.4 58 a Equivalents to palladium metal. b GC yields based on 4-chlorobenzaldehyde. 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
25、 ） ，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 5 Tatsuo Ishiyama, Tetrahedron 57 (2001) 9813-9816 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。 Table 2. Synthesis of pinacol arylboronates Entry Chloroarene Mo
26、l% a Time (h) Yield (%) b 1 4-O2NC6H4Cl 3 4 88 2 2-O2NC6H4Cl 3 48 72 3 4-NCC6H4Cl 3 4 98 4 2-NCC6H4Cl 3 48 72 5 4-OHCC6H4Cl 3 6 94 6 4-MeO2CC6H4Cl 3 6 87 7 C6H5Cl 6 48 91 8 4-MeC6H4Cl 6 48 92 9 2-MeC6H4Cl 3 48 86 10 4-MeOC6H4Cl 6 48 78 11 3-MeOC6H4Cl 6 48 92 12 2-MeOC6H4Cl 3 48 70 13 4-Me2NC6H4Cl 6
27、48 73 14 2-Chloronaphthalene 3 48 77 15 2-Chloropyridine 3 48 0 16 3-Chloropyridine 3 48 82 17 O Cl 3 48 73 18 HN Cl 3 48 72 a 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： XEDG 2 KOAc 80 oC BEDG
28、O O EDG X= Catalyst/solvent Time/h Yield% MeO I PdCl2(dppf)/DMSO 2 82 Br PdCl2(dppf)/DMSO 24 69 Br Pd (dba) 2-PCy3/dioxane 7 81 OTf PdCl2(dppf)-dppf/dioxane 13 93 OTf Pd (dba) 2-PCy3/dioxane 2 83 Me2N I PdCl2(dppf)/DMSO 6 90 Br PdCl2(dppf)/DMSO 24 23 Br Pd (dba) 2-PCy3/dioxane 6 81 2.2.1 通过二硼烷频哪酯制备芳
29、基硼酸酯示例（一） Br KOAc BB O OO O B O O Pd(dppf)Cl 2 DMSO, 80 , 98 % A flask charged with palladium catalyst (0.03 mmol), KOAc (294 mg, 3.0 mmol), and diboron (279 mg, 1.1 mmol) was flushed with nitrogen. DMSO (6 mL) and haloarene (1.0 mmol) were then added. After being stirred at 80 for an appropriate pe
30、riod, the product was extracted with benzene, washed with water, and dried over anhydrous magnesium sulfate. Kugelrohr distillation in vacuo gave the arylboronates. 2.2.2 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 B HO2C OH OH OH OH B HO2C O O toluene, reflux A solution of 4-(dihydroxyboryl)benzoic a
31、cid (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 product of sufficient purity for subsequent use. 2.3 烯基硼酸酯的制备 6 Brn-Bu n-Bu B(O i-
32、Pr)2 Br Et2O KHB(O i-Pr)3 n-BuB(O i-Pr)2 1. HBBr2 S(CH3)2 2. i-PrOH 87%89% 2.4 烷基硼酸酯的制备 7 DH D OTDS B H B OTDS H H D D B I O O OTDS H HD D Pd(dppf)Cl 2 NaOH H 2-3-(tert-Butyldimethylsiloxy)-1,2- syn -dideuteriopropyl-2-cyclohexen-1-one (syn -7). Propene cis-2 (150 mg, 0.86 mmol) was added to a solut
33、ion 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 sequentially. The mixture was ag
34、ain 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 6 Brown, H. C.; Imai, T. Organometallics 1984 , 3, 1392 1395. 7 Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998 , 63, 458 460. separ
35、ated and washed with 2 _ 25 mL of Et2O. The combined organic layers were dried over Na2SO4, filtered, 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 2 PdCl2 + 8 PPh3 + 5 NH2NH2 H2O2 Pd(P
36、Ph3)4 + 4 NH2NH2 HCl + N2 + 5 H2O A mixture of palladium dichloride (17.72 g., 0.10 mole), triphenylphosphine (131 g, 0.50 mole), and 1200 ml of dimethyl sulfoxide is placed in a single-necked, 2L, round-bottomed flask equipped with a magnetic stirring bar and a dual-outlet adapter. A rubber septum
37、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 yellow mixture is heated by means of an oil bath with stirring until complete solution occurs (ca. 140). The bath is then taken a
38、way, 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 hypodermic syringe. A vigorous reaction takes place with evolution of nitrogen. The dark solution is then immediately cooled with a wate
39、r 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 it is filtered under nitrogen on a coarse, sintered-glass funnel. The solid is washed successively with two 50 ml. portions of eth
40、anol 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 weighs 103.5-108.5 g. (90-94% yield). A melting point determination on a sample in a sealed capillary tube under nitrogen gave a deco
41、mposition point of 116 (uncorrected). This compares with a similar determination (115) performed on the product prepared by the method of Malatesta and Angoletta. Properties: The Pd(PPh3)4 complex obtained by this procedure is a yellow, crystalline material possessing moderate solubilities in benzen
42、e (50 g/L), methylene chloride, and chloroform. The compound is less soluble in acetone, tetrahydrofuran and acetonitrile. Saturated hydrocarbon solvents give no evidence 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
43、制备 PdCl2 + PPh 3 Pd(PPh 3)2Cl2 Ph-CN N2, 200 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 Pd(CH3CN)2Cl2PdCl2 + CH3CNPd(dppf)Cl2 dppf benzene To absolute acetonitrile (1950 mL) degassed v
44、ia 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 added a solution of dppf
45、(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 complex can be recrystall
46、ized from chloroform/benzene. 4Suzuki 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： aryl aryl alkyl aryl n-propyl n-propyl ethyl ethyl methyl
47、methyl 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Suz
48、uki 偶联反应的普通操作：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 di
49、oxane / H2O。 Table 3是 Suzuki 反应的常用条件 : ArX+ RB(OH) 2 ArR Pd base, solvent Table 3 The general conditions for Suzuki coupling 8 Entry Solvents Catalyst Base Temperature 1 dioxane Pd(PPh3)4K2CO3120 2 DMF Pd(PPh3)4K3PO480 3 DME / H2O Pd(PPh3)4Na2CO3refluxed 4 Toluene / H2O, MeOH Pd(PPh3)4Na2CO3refluxed 5 DMF / H2O Pd(dppf)Cl2Na2CO3120 6 MeCN / H2O Pd(PPh3)4Na2CO3refluxed 8 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,