Suzuki反应0226.docx

1、Suzuki反应0226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 31.1 Suzuki反应的通式 31.2 Suzuki反应的机理 31.3 Suzuki反应的特点及研究方向 42 有机硼试剂的合成 42.1 通过金属有机试剂制备单取代芳基硼酸 42.1.1 通过Grinard试剂制备单取代芳基硼酸示例 42.1.2 通过有机锂试剂制备单取代芳基硼酸示例 52.2 通过二硼烷频哪酯制备芳基硼酸酯 62.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一） 92.2.2 通过二硼烷频哪酯制备芳基硼酸酯示例（二） 102.2.3 通

2、过芳基硼酸转化为芳基硼酸酯 102.3 烯基硼酸酯的制备 102.4 烷基硼酸酯的制备 103 催化剂的制备 113.1 Pd(PPh3)4的制备 113.2 Pd(PPh3)2Cl2的制备 123.3 Pd(dppf)Cl2的制备 124 Suzuki偶联的应用 124.1 普通的芳卤和芳基硼酸的Suzuki偶联 134.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例 144.2 大位阻芳基硼酸参与Suzuki偶联反应 144.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应 154.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联 164

3、.3.2 带着酯基底物的Suzuki偶联反应示例（一） 164.3.3 带着酯基底物的Suzuki偶联反应示例（二） 174.4 杂环芳基硼酸参与Suzuki偶联反应 174.5烷基硼酸参与Suzuki偶联反应 184.6烯基硼酸参与Suzuki偶联反应 194.7 Triflate参与Suzuki偶联反应 194.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例 204.7.2 芳基的Triflate与芳基硼酸偶联示例 204.8 芳基氯参与Suzuki偶联反应 214.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一） 214.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二） 224

4、.9 镍催化体系用于Suzuki偶联反应 224.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例 224.10 其他方法 234.10.1 直接Pd/C用于 Suzuki偶联反应示例 234.10.2 直接Pd(OAc)2用于 Suzuki偶联反应示例 231 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。 Suzuki反应的通式1.2 Suzuki反应的机理Suzuki 偶联反应的催化循

5、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）

6、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: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。2.1.1 通过Gr

7、inard试剂制备单取代芳基硼酸示例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 condenser fitted with an argon

8、 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

9、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

10、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 0C, and the eth

11、er 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 sep

12、arated 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

13、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 the mother liquor 3-4 times prov

14、ides 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, trimethylbora

15、te (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 tha

16、t was used without further purification.2.2 通过二硼烷频哪酯制备芳基硼酸酯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

17、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。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，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)

18、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%)EntryLigandLigand (equiv.)aYield (%)b1None12PPh32.4193P(o-MeC6H4)32.4364P(p-MeOC6H4)32.4445dppfc1.118641.178752.468861.110971.17110PCy32.49

19、411P(t-Bu)32.458a 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），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

20、，2-氯吡啶(Entry 15)不能得到目标产物。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 arylboronatesEntryChloroareneMol%aTime (h)Yield (%)b14-O2NC6H4Cl348822-O2NC6H4Cl3487234-NCC6H4Cl349842-NCC6H4Cl3487254-OHCC6H4Cl369464-MeO2CC6H4Cl36877C6H5Cl6489184-MeC6H4Cl6489292-MeC6

21、H4Cl34886104-MeOC6H4Cl64878113-MeOC6H4Cl64892122-MeOC6H4Cl34870134-Me2NC6H4Cl64873142-Chloronaphthalene34877152-Chloropyridine3480163-Chloropyridine3488217348731834872a 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

22、得到较好的结果，如下表所示：EDGX=Catalyst/solventTime/hYield%MeOIPdCl2(dppf)/DMSO282BrPdCl2(dppf)/DMSO2469BrPd (dba) 2-PCy3/dioxane781OTfPdCl2(dppf)-dppf/dioxane1393OTfPd (dba) 2-PCy3/dioxane283Me2NIPdCl2(dppf)/DMSO690BrPdCl2(dppf)/DMSO2423BrPd (dba) 2-PCy3/dioxane681 2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一）A flask charged wit

23、h 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 an

24、hydrous 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

25、. 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2.4 烷基硼酸酯的制备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 solutio

26、n 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 agai

27、n 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 separated and washed with 2 _ 25 mL of Et2O. The combined organic layers were dried over Na2SO4, filtered, and reduced in vacuo. Purific

28、ation 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 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-

29、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

30、 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

31、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 w