最新精选Suzuki反应药明康德.docx

1、最新精选Suzuki反应药明康德最新【精选】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。 Suzuki反应的通式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(I

2、I)）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）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Su

3、zuki 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Grinard试剂制备单取代芳基硼酸示例A 500-mL, three-necked, round-bottomed flask con

4、taining 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 inlet adapter. The system is flame-dried and flushed with argon.

5、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

6、 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

7、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 ether solution of (3,4,5-trifluorophenyl)magnesium bromide prepared a

8、bove 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 portio

9、ns 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 (65C) ethyl acetate, allowed to cool to room temperature, and

10、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

11、.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, trimethylborate (0.2 mL, 1.6 mmol) was added in one portion. The mixture was wa

12、rmed 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对于分子中带有

13、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

14、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) with 4-chlorobenzaldehyde (1.0 mmol) in dioxane (6 ml) at 80C for

15、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)32.4445dppfc1.118641.178752.468861.110971.17110PCy32.49411P(t-Bu)32.458a Equivalents to palladium metal.b GC yields based

16、 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，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

17、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-MeC6H4Cl34886104-MeOC6H4Cl64878113-MeOC6H4Cl64892122-MeOC6H4Cl34870134

18、-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中会得到较好的结果，如下表所示：EDGX=Catalyst/solventTime/hYield%MeOIPdCl2(dppf)/DMS

19、O282BrPdCl2(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 with palladium catalyst (0.03 mmol), KOAc (294 mg, 3.0 mmol), and dib

20、oron (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 th

21、e 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. The concentrate was triturated with diethyl ether and filtered t

22、o 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 solution of 9-BBN (126 mg, 1.03 mmol) in THF (15 mL) at 0 C. The reaction

23、 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 mixtur

24、e 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. Purification by flash chromatography (10:90 EtOAc:hexane) yielded pure pr

25、oduct 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-bottomed flask equipped with a magnetic stirring bar and a dual-ou

26、tlet 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.

27、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

28、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 w

29、ith 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 t

30、ube 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 possessing m

31、oderate 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20