Suzuki反应-药明康德

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

药明康德内部保密资料

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

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

4 Suzuki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

药明康德内部保密资料

Page 1 of 25

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

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

药明康德内部保密资料 Page 2 of 25

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

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。

ZB(OH)2+Br3 mol% [Pd(PPh3)4]aq Na2CO3benzene or toluenerefluxZ

Suzuki反应的通式

R1BY2+R2X[Pd]baseR1R2BY2 = B(OR)2, 9-BBN, B(CHCH3CH(CH3)2)X = I, Br, Cl, OSO2(CnF2n+1), n = 0,1,4R1 = aryl, alkenyl, alkylR2 = aryl, alkenyl, alkynyl, benzyl, allyl, alkyl[Pd] = Pd(PPh3)4, Pd(dppf)Cl2base = Na2CO3, 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)。

药明康德内部保密资料

Page 3 of 25

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

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)3H3OArB(OH)2

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(OPri)3HClArB(OPri)2

2.1.1 通过Grinard试剂制备单取代芳基硼酸示例

FMgFFBrEt2OTHFFB(OMe)3FB(OH)2F

A 500-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 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 307 and ref 12.

2

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.; Rangaishenvi, M. V. Tetrahedron Lett. 1990, 49, 7113, 7115.

药明康德内部保密资料

Page 4 of 25

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

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3

TMS1. nBuLi, THF -78C, 15min2. B(OMe)3I -78C-25C, 30min3. H+/HCloooTMS(HO)2B

3

Chem. Eur. J. 2003, 9, 4430-4441

Page 5 of 25

药明康德内部保密资料

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

nBuLi (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

(RO)2B-B(OR)2XXPd(dppf)Cl2KOAcDMSO, 80℃XB(OR)2

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Ishiyama4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：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。 4

Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.

药明康德内部保密资料

Page 6 of 25

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

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 of bis(pinacolato)diboron (2, 1.1 mmol) with 4-chlorobenzaldehyde (1.0 mmol) in dioxane (6 ml) at 80°C 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 1 2 3 4 5 6 7 8 9 10 11 a

Ligand None PPh3 P(o-MeC6H4)3 P(p-MeOC6H4)3 dppfc 4 5 6 7 PCy3 P(t-Bu)3 Ligand (equiv.)a 2.4 2.4 2.4 1.1 1.1 2.4 1.1 1.1 2.4 2.4 Yield (%)b 1 19 36 44 18 78 68 10 71 94 58 Equivalents to palladium metal.

GC yields based on 4-chlorobenzaldehyde.

bc

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

5

Tatsuo Ishiyama, Tetrahedron 57 (2001) 9813-9816

Page 7 of 25

药明康德内部保密资料

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

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 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 aChloroarene 4-O2NC6H4Cl 2-O2NC6H4Cl 4-NCC6H4Cl 2-NCC6H4Cl 4-OHCC6H4Cl 4-MeO2CC6H4Cl C6H5Cl 4-MeC6H4Cl 2-MeC6H4Cl 4-MeOC6H4Cl 3-MeOC6H4Cl 2-MeOC6H4Cl 4-Me2NC6H4Cl 2-Chloronaphthalene 2-Chloropyridine 3-Chloropyridine ClOClHNMol%a 3 3 3 3 3 3 6 6 3 6 6 3 6 3 3 3 3 3 Time (h) 4 48 4 48 6 6 48 48 48 48 48 48 48 48 48 48 48 48 Yield (%)b 88 72 98 72 94 87 91 92 86 78 92 70 73 77 0 82 73 72 b

Mol% of catalyst. 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

药明康德内部保密资料 Page 8 of 25

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

Pd(dba)2/2.4PCy3(3-6mol %)在dioxone中会得到较好的结果，如下表所示：

EDGX2KOAc80oCOEDGBO

EDG MeO Me2N

X= I Br Br OTf OTf I Br Br Catalyst/solvent PdCl2(dppf)/DMSO PdCl2(dppf)/DMSO Pd (dba) 2-PCy3/dioxane PdCl2(dppf)-dppf/dioxane Pd (dba) 2-PCy3/dioxane PdCl2(dppf)/DMSO PdCl2(dppf)/DMSO Pd (dba) 2-PCy3/dioxane Time/h 2 24 7 13 2 6 24 6 Yield% 82 69 81 93 83 90 23 81 2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一）

OOBBOOBrPd(dppf)Cl2OBOKOAcDMSO, 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 period, the product was extracted with benzene, washed with water, and dried over anhydrous magnesium sulfate. Kugelrohr distillation in vacuo gave the arylboronates.

药明康德内部保密资料 Page 9 of 25

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.

药明康德内部保密资料

Page 10 of 25

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

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

药明康德内部保密资料 Page 11 of 25

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

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：

药明康德内部保密资料

Page 12 of 25

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

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.

Page 13 of 25

药明康德内部保密资料

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

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.

Page 14 of 25

药明康德内部保密资料

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

FConditionsCNClNCNNHFClBrNNHROBROHOBOHCNOBOCNOBOCN0 B 0 %

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.

OBOCHO+ArXPd(PPh3)4K3PO4DMF, 80℃ArCHO

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:

药明康德内部保密资料 Page 15 of 25

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

4.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联

OONHBr+OBO(PH3P)4Pd IIIK2CO3 IVH2O Vdioxane VIrefluxOONHIIIVII

To a solution of 3.862 g of I and 3.401 g of II in 80 mL of 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 residue 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 带着酯基底物的Suzuki偶联反应示例（一）13

OHBrMeO2CFBOHPd(dppf)Cl2Na2CO3, DCM, refluxMeO2CF

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 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 chromatography on silica gel with 10percent ethyl acetate/hexanes to provide additional product.

13

Patent; Augeri, David J.; Publ.: US2002/55631 A1 (2002/05/09)

Page 16 of 25

药明康德内部保密资料

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

4.3.3 带着酯基底物的Suzuki偶联反应示例（二）14

COOEtB(OH)2COOMe1.Suzuki-couplingClNCOOMe2.EtOH, HCl, refluxHNNCOOEtHN

Into 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-dicarboxylic acid dimethyl ester (3.44g, 15.0 mmol) were added into this solvent and the resulting mixture was stirred at r.t. under argon for 1 hour. A solution of indole-4-boronic acid (1.86g, 11.5 mmol) in 50 ml EtOH and a solution of 2M aqueous Na2CO3 (11.5 ml) was added into the reaction mixture at r.t. under argon. The mixture was heated under argon with vigorous stirring at 105?C for 8 hours. The reaction mixture was cooled and brine (200 ml) was added. The organic layer was separated and aqueous layer extracted with additional CH2Cl2 (2x100 ml). The combined organic layer was dried over Na2SO4 and evaporation of the solvent left a yellowish solid. Purification of the crude material through a short plug of silica gel (hexane:ethyl acetate, 1:2) afforded a yellow solid. The TLC of this material showed it to be a mixture of three different compounds due to ester exchange. This solid was dissolved in 500 ml EtOH and the solution was stirred overnight at r.t. in the presence of catalytic HCl in diethyl ether. A single compound (3.54g) was obtained (mp. 212.3-213.0°C) in 91.0% yield.

4.4 杂环芳基硼酸参与Suzuki偶联反应

杂环芳基硼酸参与Suzuki偶联反应同样可以得到好的结果15.

MeOOCNBr+O2NB(OH)2Pd(PPh3)4aq. Na2CO3benzeneNMeOOCNO2

1415

http://www.rhodium.ws/chemistry/lysergic.hendrickson.html

a) Thompson, W. J.; Gaudino, J . J . Org. Chem. 1984, 49, 5237. b) Thompson, W. J.; Jones, J. H.; Lyle, P. A,; Thies,

J. E. J . Org. Chem. 1988, 53, 2052.

药明康德内部保密资料 Page 17 of 25

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

3-吡啶基二乙基硼烷是一个对空气和水份稳定的化合物, 可以用来作杂环的芳化反应16.

MeOCNBr+NBEt2Pd(PPh3)4aq. NaOH,/ Bu4NClTHFMeOCNN

一般说来2-噻吩硼酸，3-吡啶硼酸做Suzuki结果都不是太理想。

4.5烷基硼酸参与Suzuki偶联反应

对于芳基卤和甲基硼酸(酯)参与的Suzuki反应, 收率一般都很低。一个改进的方法是用剧毒的TlOH或Tl2CO3作碱, Suzuki反应的收率有提高17。近来有报道用甲基三氟硼酸钾代替甲基硼酸, 取得了较好的结果。这种方法突出的优点是试剂易于制备, 对空气稳定, 并且用于Suzuki偶联反应一般可以得到较好的结果18。

ArOTfMeBF3K+orArXCs2CO3THF / H2O= 1: 1Pd(dppf)Cl2ArMe

Entry ArBr or ArOTf Product Yield Entry ArBr or ArOTf Product Yield 1 TfOO O 85% 8 BrCNCN60% 92% 2 BrO O 80% 9 BrO O 57% CO2MeCO2Me3 BrO O61% 10 Br 16

Ishikura, M.; Kamada, M.; Terashima, M. Synthesis 1984, 936.

17

Sato, M.; Miyaura, N.; Suzuki, A. Chem. Lett. 1989, 1405-1408 18

Molander, G. A.; Yun C. S.; Ribagorda, M.; Biolatto B.. J . Org. Chem. 2003, 68, 5534-5539.

药明康德内部保密资料 Page 18 of 25

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

Br4 TfONO2 NO2 85% 11 F3CF3CNO285% O2NNO25 BrNO2 NO2 77% 12 Br 83% O2N6 BrNHAc NHAc 67% 13 ClN32% N 7 BrCN CN 68%

4.6烯基硼酸参与Suzuki偶联反应

OOBrB(CH2)8CNPdCl2(dppf) (3 mol%)K2CO3 (2 equiv)DMF, THF, 50oC81%Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki, A. J. Am. Chem. Soc.1989, 111, 314–321.

(CH2)8CN

4.7 Triflate参与Suzuki偶联反应

因为三氟甲基磺酸酯可以由相应的酚或者酮方便地制备, 这个试剂参与Suzuki偶联反应吸引了越来越多的科学研究者的兴趣。

ArB(OH)2OTfBocHNCO2MePd(PPh3)4K2CO3toluene90℃BocHNCO2Me75-94%Ar

三氟甲基磺酸酯和芳基硼酸的偶联反应有时候会因为在反应初期, 催化剂配体PPh3容易和triflate反应, 从而导致催化剂分解破坏为钯黑。如果在反应体系中加入和催化剂等当量的LiBr 或KBr就足以阻止这种分解反应。

药明康德内部保密资料 Page 19 of 25

经典合成反应标准操作—Suzuki反应

Pd(0)LnROTf[R-Pd(I)][TfO]LnPPh3 药明康德新药开发有限公司

LiBrR-Pd-BrnL2[Ph3PR] [TfO]+Pd(0)

4.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例19

CO2MeOTfHOBOHPd(PPh3)4Na2CO3 eq., EtOH, tolueneCO2MeFF

To 1.5 g (4.8 mmol) of product in 12.5 mL of toluene at room temperature was added 0.28 g (0.24 mmol, 0.05 eq. ) of Pd (PPh3)4. After stirring for 5 min, 1.1 g (5.7 mmol, 1.2 eq. ) of 4-fluorophenylboronic acid in 5.5 mL of EtOH followed by 11.5 mL of 2 M aqueous Na2CO3 were added. After heating at 90 .deg.C for 12 h the reaction was judged complete, cooled and diluted with Et2O (100 mL) and water (50 mL). The resulting layers were separated and the aqueous layer extracted twice with Et2O (100 mL). The combined organic layers are dried over MgS04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield the desired methyl 4-ethyl-4'-fluoro-1, 1'- biphenyl-2-carboxylate 4.7.2 芳基的Triflate与芳基硼酸偶联示例20

ClTfOOTfHOBOHPd(PPh3)4Na2CO3 eq., THFClCl

Synthesis of 9,9-bis(4'-chloro-biphenyl-4-yl)fluorene: 16 g of

9,9-bis[4-(trifluoromethylsulfonyl)phenyl]fluorene, 100 ml of tetrahydrofuran, 62 g of a 20percent sodium carbonate aqueous solution, 8.54 g of 4-chlorophenylboronic acid, and 0.6

1920

Patent; ELAN PHARMACEUTICALS, INC.; Publ.: WO2005/95326 A2 (2005/10/13) Patent; Tosoh Corporation; Publ.: EP1400578 A1 (2004/03/24)

Page 20 of 25

药明康德内部保密资料

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

g of tetrakis(triphenylphosphine)palladium were placed in a 300 ml four-necked flask, and the mixture was heated at 70.deg.C. The resulting mixture was aged at the same temperature for 18 hours, and the reaction mixture was then cooled to room temperature and subjected to liquid separation. An organic phase was washed with a saturated ammonium chloride aqueous solution and saturated salt water, and the resulting organic phase was concentrated and recrystallized from tetrahydrofuran to obtain 11.4 g of a white powder.

4.8 芳基氯参与Suzuki偶联反应

Mitchell等报导了用dppb作钯的配体，能够有效地催化氯代芳杂类同芳基硼酸进行Suzuki反应，产率高达98%; 之后Wang Shen等用三环已基磷(PCy3)作钯的配体，发现此配体催化剂能够最有效地激活芳氯键，这可能是由于三环已基磷比三苯基磷有更多的电子，因而可以增加钯氧化插入芳氯键的能力，同时还发现在Pd(PCy3)Cl2催化下，邻对位吸电子取代芳基氯能更有效的进行反应。

4.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一）21

OHBOHClOOPd(Cy3)2Cl2, CsF, NMP

OO

The following is a typical experimental procedure. A mixture of methyl trarts-3shlorociunamate

(entry

18,

Table

2)

(393.2

mg,

2

mmol),

dichlorobis(tricyclobezylphosphine) palladium(73.8 mg, 0.10 mol), phenylboronic acid (292.6 mg. 2.4 mmol), and cesium fluoride (607 mg, 4.0 mmol) in 1-methyl-2-pyrrolidinone (NMP, 5 mL) was degassed by purging with nitrogen. The mixture was then heated at 100 ℃ for 10 hours. The mixture was then partitioned between ethyl acetate (90 mL) and water (20 mL). The organic layer was separated, washed with water, dried, and concentrated} The residue was then purified by column chromatography eluting with 50/50/5 toluene/hexane/ether to give the coupled product (466 mg.98%).

21

Tetrahedron Letter: Vol. 38, No. 32, pp. 5575-5578, 1997

Page 21 of 25

药明康德内部保密资料

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

4.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二）22

(HO)2BCOCH3H3CO2CCl(1.5 equiv)Pd(OAc)2 (1 mol%)P(t-Bu)2(2 mol%)H3CO2CCOCH3

1.0 equiv of aryl chloride, 1.5 equiv of boronic acid, 3.0 equiv of KF, cat. Pd(OAc)2 , cat. (two ligands per Pd center), THF (1 mL per mmol of aryl chloride), room temperature. Reaction times t have not been minimized. 4.9 镍催化体系用于Suzuki偶联反应

Syun Satio等研究发现,在零价镍催化下氯代芳烃和芳基硼酸在80℃可高产率地发生偶联反应，零价镍自NiCl2(dppf) （10 mol%）和n-BuLi(40 mol%)―一锅‖反应来制备，而氯代芳烃可带有各种吸电子或给电子基因. 此方法中镍催化剂成本低，同时选用廉价的氯代芳烃作为反应物，因而有很高的工业应用价值；也有人研究使用NiCl2(PPh3)2来催化烷基取代硼酸盐和溴代物的偶取反应，在室温下以80%的高产率合成了生物活性化合物。

4.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例23

10 mol% of NiCl2(dppf) + 4 BuLiZK3PO4, dioxane at 80°CZB(OH)2+ClZ = 4-CN, 4-CHO, 2- or 4-CO2Me, 4-COCH3, 4-NHAc, 3- or 4-CH3, 3- or 4-OMe, 4-NH2

Representative procedure: A solution of BuLi in hexane (0.4 mmol) was added to a solution of NiCl2(dppf) (0.1 mmol) in dioxane (4 ml) at room temperature to give a red solution of nickel(0) complex. After being stirred for 10 min, phenylboronic acid (1.1 mmol), K3PO4 (3.0 mmol), a chloroarene (1.0 mmol and an additional dioxane (2 ml) were added to the flask. The reaction mixture was stirred at 84 ℃ for the period indicated in the Table 2 The product

2223

Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1999, 38, 2413–2416. Tetrahedron Letter: Vol.37, No. l7, pp. 2993-2996, 1996

Page 22 of 25

药明康德内部保密资料

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

was isolated by chromatography over silica gel.

4.10 其他方法

研究发现，对某些碘代物，一些无磷配体催化剂可以在较为温和的条件下高效的催化反应，如PdCl2、Pd(OAc)2、Pd/C等。同时，也可以避免反应中配体所形成的杂质对产品分离过程产生的困扰。

4.10.1 直接Pd/C用于 Suzuki偶联反应示例

Hiroa24 等以水作溶剂，室温下Pd./C 催化碘代苯酚与芳基硼酸的Suzuki 偶联反应取得了非常好的结果。 这个方法因为号称清洁生产，对大规模生产具有很大意义。

HO+XAr(OH)20.3 mol% Pd/C300 mol% K2CO3H2O, r.t., 12 h, 77%~99%HOAr

D. S. Ennis25 等用Pd /C 做催化剂大批量的进行Suzuki-coupling反应，以生产抗抑郁药物，SB-245570。

CO2HBrCO2HPd / CNONa2CO3, MeOH /H2Oreflux, 91%N6.2 kg4.4 kg6.3 kgOB(OH)2

4.10.2 直接Pd(OAc)2用于 Suzuki偶联反应示例26

OHBOH+IOCH3Pd(OAc)2K2CO3, acetoneH2oOCH3

4-Methoxy-2'-methylbiphenyl . o-Tolylboronic acid, 10.0 g (73.6 mmol), 16.8 g (71.8 mmol) of 4-iodoanisole, and 200 mL of acetone are combined in a 1-L, three-necked flask equipped

2425

Sakurai, H. J. Org. Chem. 2002, 67, 2721

D. S. Ennis，Org. Process Res. Dev. 1999, 3, 248 26

Felix E. Goodson, Organic syntheses, Coll. Vol. 10, p.501; Vol. 75,p.61

药明康德内部保密资料

Page 23 of 25

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

with an efficient stirbar, two stoppers, and a reflux condenser attached to a gas-flow adapter with a stopcock. Potassium carbonate, 25.0 g (0.180 mol), is dissolved in 200 mL of water in a separate 250-mL Schlenk flask. In a third flask (25-mL Schlenk flask) 3.30 mg (0.02 mmol, 0.2%) of palladium acetate is dissolved in 10 mL of acetone . All three flasks are then thoroughly degassed by four freeze-pump-thaw cycles. Under an argon back flow, one of the stoppers on the three-necked flask is replaced with a rubber septum, and the carbonate and catalyst solutions are added via cannula to form a biphasic mixture. The top layer turns brown upon addition of the catalyst. The septum is replaced with the glass stopper and three additional freeze-pump-thaw cycles are applied. The flask is then backfilled with argon, and the reaction is brought to reflux under a positive argon pressure. After 2 hr at reflux the heat source is removed and the reaction is allowed to cool. By this time the brown color has faded and the reaction is a triphasic mixture with copious amounts of palladium black floating between the layers. The reaction is transferred to a 1-L separatory funnel and extracted into diethyl ether (3 × 100 mL). The organic layers are combined, washed with water (1 × 100 mL) saturated with sodium chloride , and dried over magnesium sulfate . Solvent is removed with a rotary evaporator to yield a yellow oil which is distilled (125-130°C, 0.10 mm) to give 12.8 g of 4-methoxy-2'-methylbiphenyl as a colorless oil (90.3% yield).

The End

药明康德内部保密资料 Page 24 of 25

本文来源：https://www.bwwdw.com/article/ig06.html