Suzuki反应-药明康德.doc

1、药明康德内部保密资料 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 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 药明康德内部保密资料 Page 1 of 25 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

2、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

3、反应示例 .14 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 药明康德内部保密资料 Page 2 of 25 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

4、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

5、 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 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 药明康德内部保密资料 Page 3 of 25 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 Br Z Z+ 3 mol% Pd(Ph3)4aq Na 2CO3benzene o

6、r toluenereflux Suzuki 反应的通式 R1BY2 R2XPd R1R2+ base BY2 = B(OR)2, 9-BN, B(CHCH3CH(CH3)2)X = I, Br, Cl, OSO2(CnF2n+1), n = 0,1,4R1 = aryl, alkenyl, alkyl R2 = aryl, alkenyl, alkynyl, benzyl, alyl, alkylPd = Pd(Ph3)4, Pd(pf)Cl2base = Na 2CO3, NaOCH2CH3, TIOH, N(CH2CH3)3, K3PO4 1.2 Suzuki 反应的机理 Suzuki

7、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)。 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 药明康德内部保密资料 Page 4 of 25 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

8、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)3 ArB(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

9、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)3 ArB(OPri)2HCl 2.1.1 通过 Grinard 试剂制备单取代芳基硼酸示例 F FF Br Mg B(OMe)3Et2O THF FFF B(OH)2 1 Gerrard, W. The Chemistry ofBoron; Academic: New York, 1961. Muetterties, E. L. The Chemistry of

10、 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-Car

11、bon 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. 经典合成反应标准操

12、作Suzuki 反应 药明康德新药开发有限公司 药明康德内部保密资料 Page 5 of 25 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 magnetic stirring bar, and a reflux

13、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- trifluoro

14、benzene (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

15、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 mixtu

16、re 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 saturated ammonium chloride sol

17、ution. 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 di

18、ssolved 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. Further recrystallization of

19、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 -78oC, 15min2. B(OMe)3 -78oC-25oC, 30min3. H+/HCl 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 药明康德内部保密资料 Page 6 of 25 nBuLi (1.6_ in hexane, 1 mL, 1.6 mm

20、ol) 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 HC

21、l 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 XX (RO)2B-B(OR)2Pd(dppf)Cl2 KOAcDMSO, 80 B(OR)2X 对于分子中带有酯基、氰基、硝基、

22、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：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K 3PO4或K 2CO3这些碱性略强的 3 Chem. Eur. J. 2003, 9, 4430-4441

23、 4 Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. 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 药明康德内部保密资料 Page 7 of 25 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)Cl 2一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

24、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 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.)

25、a Yield (%)b 1 None 1 2 PPh3 2.4 19 3 P(o-MeC6H4)3 2.4 36 4 P(p-MeOC6H4)3 2.4 44 5 dppfc 1.1 18 6 4 1.1 78 7 5 2.4 68 8 6 1.1 10 9 7 1.1 71 10 PCy3 2.4 94 11 P(t-Bu)3 2.4 58 a Equivalents to palladium metal. b GC yields based on 4-chlorobenzaldehyde. c 1,1-Bis(diphenylphosphino)ferrocene. 如Table 2所示

26、，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NO 2、CN、CHO和CO 2Me（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 5 Tatsuo Ishiyama, Tetrahedron 57 (2001) 9813-9816 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 药明康德内部保密资料 Page 8 of 25 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

27、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 Mol%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

28、-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 48 73 14 2-Chloronaphthalene 3 48 77 15 2-Chloropyridine 3 48 0 16 3-Chloropyridine 3 48 82 17 OCl 3 48 73 18 HNCl 3 48 72 a Mol% of catalyst. b GC yields based on chloroaren

29、es. 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 药明康德内部保密资料 Page 9 of 25 对于一些富电子的芳基氯化物和碘化物，用Pd(dppf)Cl 2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 2KOAc80oC BEDG OO 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

30、 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基硼酸酯示例（一） Br KOAcBBOOOO BOOPd(pf)Cl2DMS, 80, 98 % A flask charged with palladium catalyst (0.03 mmol), KOAc (294 mg, 3.0 m

31、mol), 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

32、vacuo gave the arylboronates. 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 药明康德内部保密资料 Page 10 of 25 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 OHOH OHOH B HO2C O O toluene, reflux A solution of 4-(dihydroxyboryl)benzoic acid (1.66 g, 10 mmol) and pinacol (12 mmol) in toluene (70 m) was refluxed in a

33、 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(Oi-Pr)2Br Et2OKHB(Oi-Pr)3n-Bu B(Oi-Pr)21. HBr2S(CH3)22. i-PrOH87% 89% 2.4 烷基硼酸酯的制备

34、7 DHDOTDS B HB OTDSH HDB IO O OTDS HHDDPd(pf)Cl2NaOHH 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.

35、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 6 Brown, H. C.; Imai,

36、T. Organometallics 1984, 3, 13921395. 7 Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458460. 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 药明康德内部保密资料 Page 11 of 25 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 o

37、rganic 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 PdCl 2 + 8 Ph3 + 5 NH2NH2 H2O 2 Pd(Ph3)4 + 4 NH2NH2 HCl + N2 + 5 H2O A mixture of palladi

38、um 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 outl

39、ets, 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 approxima

40、tely 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

41、 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 d

42、ried 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 wi

43、th a similar determination (115 ) performed on the product prepared by the method of Malatesta and Angoletta. 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 药明康德内部保密资料 Page 12 of 25 Properties: The Pd(PPh3)4 complex obtained by this procedure is a yellow, crystalline material possessing moderate solubilities in b

44、enzene (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)

45、2Cl2 的制备 PdCl2 + PPh3 Pd(PPh3)2Cl2Ph-CNN2, 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(CH 3CN)2Cl2PdCl2 + CH3CN Pd(pf)Cl2dpfbenzene To absolute acetonitrile (1950 mL) degassed via

46、 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 (4

47、0.6 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 recrystalli

48、zed 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 -。 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 药明康德内部保密资料 Page 13 of 25 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 ethyl