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
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
OHBHO2COHOHOHtoluene, refluxHO2COBO
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 product of sufficient purity for subsequent use. 2.3 烯基硼酸酯的制备6
1. HBBr2·S(CH3)22. i-PrOH87%n-BuBrB(Oi-Pr)2KHB(Oi-Pr)3Et2O89%n-BuBrn-BuB(Oi-Pr)2
2.4 烷基硼酸酯的制备7
OOTDSDHDBHHBOTDSDHDHBIOPd(dppf)Cl2NaOHDHOTDSHD
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 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 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
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.
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separated 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(PPh3)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 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 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 hypodermic 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 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 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 decomposition 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
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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 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
PdCl2 + PPh3Ph-CNN2, 200 ℃ Pd(PPh3)2Cl2
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
PdCl2 + CH3CNPd(CH3CN)2Cl2dppfbenzenePd(dppf)Cl2
To absolute acetonitrile (1950 mL) degassed via three vacuum/nitrogen ingress cycle was added dichloropalladium (13 g, 73 mmol), the mixture was refluxed at 90~100 °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 (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 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：
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aryl–aryl > alkyl–aryl > n-propyl–n-propyl > ethyl–ethyl > methyl–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Suzuki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dioxane / H2O。 Table 3是Suzuki反应的常用条件:
ArX+RB(OH)2PdArRbase, solvent
Table 3 The general conditions for Suzuki coupling8
Entry 1 2 3 4 5 6 8
Solvents dioxane DMF DME / H2O Toluene / H2O, MeOH DMF / H2O MeCN / H2O Catalyst Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(PPh3)4 Pd(dppf)Cl2 Pd(PPh3)4 Base K2CO3 K3PO4 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Temperature 120℃ 80℃ refluxed refluxed 120℃ refluxed 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.
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4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例9
OHBrBrOBOHPd(PPh3)4Na2CO3, DME, refluxBrO
Under an argon 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 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 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10。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11。
B(OH)2Pd(PPh3)4+ArXaq. Ba(OH)2DME, 80℃Ar
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12。
9
Patent; Takeda Chemical Industries, Ltd.; Publ.: US6518257 B1 (2003/02/11)
a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207. b) Kelly, T. R.; Garcia, A.; Lang, F.; Walsh, J. J.; Bhaskar, K.
10
V.; Boyd, M. 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.
11
Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
12
J. Organomet. Chem. 2002, 653, 269.
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