1、經(jīng)典合成反應標準操作Suzuki反應 藥明康德新藥開發(fā)有限公司經(jīng)典化學合成反應標準操作Suzuki 反應編者：劉德軍、武偉藥明康德新藥開發(fā)有限公司化學合成部目 錄1 前言31.1 Suzuki反應的通式31.2 Suzuki反應的機理31.3 Suzuki反應的特點及研究方向42 有機硼試劑的合成42.1 通過金屬有機試劑制備單取代芳基硼酸42.1.1 通過Grinard試劑制備單取代芳基硼酸示例42.1.2 通過有機鋰試劑制備單取代芳基硼酸示例52.2 通過二硼烷頻哪酯制備芳基硼酸酯62.2.1 通過二硼烷頻哪酯制備芳基硼酸酯示例（一）92.2.2 通過二硼烷頻哪酯制備芳基硼酸酯示例（二）1

2、02.2.3 通過芳基硼酸轉化為芳基硼酸酯102.3 烯基硼酸酯的制備102.4 烷基硼酸酯的制備103 催化劑的制備113.1 Pd(PPh3)4的制備113.2 Pd(PPh3)2Cl2的制備123.3 Pd(dppf)Cl2的制備124Suzuki偶聯(lián)的應用124.1 普通的芳鹵和芳基硼酸的Suzuki偶聯(lián)134.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 體系Suzuki偶聯(lián)反應示例144.2 大位阻芳基硼酸參與Suzuki偶聯(lián)反應144.3 含敏感功能團的芳基硼酸（酯）參與Suzuki偶聯(lián)反應154.3.1 芳基硼酸頻哪酯和芳基鹵代物的Suzuki偶聯(lián)164.3.2 帶

3、著酯基底物的Suzuki偶聯(lián)反應示例（一）164.3.3 帶著酯基底物的Suzuki偶聯(lián)反應示例（二）174.4 雜環(huán)芳基硼酸參與Suzuki偶聯(lián)反應174.5烷基硼酸參與Suzuki偶聯(lián)反應184.6烯基硼酸參與Suzuki偶聯(lián)反應194.7 Triflate參與Suzuki偶聯(lián)反應194.7.1芳基的三氟甲基磺酸酯與芳基硼酸偶聯(lián)示例204.7.2 芳基的Triflate與芳基硼酸偶聯(lián)示例204.8 芳基氯參與Suzuki偶聯(lián)反應214.8.1鈀催化下芳基氯參與Suzuki偶聯(lián)反應示例（一）214.8.2鈀催化下芳基氯參與Suzuki偶聯(lián)反應示例（二）224.9 鎳催化體系用于Suzuki偶

4、聯(lián)反應224.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯參與Suzuki偶聯(lián)反應示例224.10 其他方法234.10.1 直接Pd/C用于 Suzuki偶聯(lián)反應示例234.10.2 直接Pd(OAc)2用于 Suzuki偶聯(lián)反應示例231 前言1.1 Suzuki反應的通式在鈀催化下，有機硼化合物與有機鹵素化合物進行偶聯(lián)反應，這就提供了一類常用和有效的合成碳-碳鍵化合物的方法，我們稱之為Suzuki 偶聯(lián)反應，或Suzuki-Miyaura 偶聯(lián)反應。 Suzuki反應的通式1.2 Suzuki反應的機理Suzuki 偶聯(lián)反應的催化循環(huán)過程通常認為先是Pd(0)與鹵代芳烴發(fā)生氧

5、化-加成反應生成Pd(II) 的絡合物 1，然后與活化的硼酸發(fā)生金屬轉移反應生成Pd(II)）的絡合物 2，最后進行還原-消除而生成產(chǎn)物和Pd(0)。 1.3 Suzuki反應的特點及研究方向這類偶聯(lián)反應有一些突出的優(yōu)點，比如：1.反應對水不敏感； 2. 可允許多種活性官能團存在；3. 可以進行通常的區(qū)域和立體選擇性的反應，尤其是，這類反應的無機副產(chǎn)物是無毒的并且易于除去，這就使得其不僅適用于實驗室而且可以用于工業(yè)化生產(chǎn)。其缺點是氯代物（特別是空間位阻大的氯代物）及一些雜環(huán)硼酸反應難以進行。目前，Suzuki 偶聯(lián)反應的研究主要在以下幾個方面：（1）合成并篩選能夠在溫和的條件下高效催化鹵代芳烴

6、（特別是氯代芳烴）的配體；（2）多相催化體系的Suzuki偶聯(lián)反應研究；（3）應用于Suzuki 偶聯(lián)反應的新合成方法研究。2 有機硼試劑的合成2.1 通過金屬有機試劑制備單取代芳基硼酸經(jīng)典合成單取代芳基硼酸(酯)的方法是用格氏試劑或鋰試劑和硼酸酯反應來制備 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.; Sokoli

7、k, 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 30

8、7 and ref 12.:用這種經(jīng)典方法的缺點是單取代芳基硼酸酯有進一步生成二取代硼酸，甚至三烷基硼的可能，因此反應須在低溫下進行。解決這個問題的一個有效的辦法是使用硼酸三異丙酯和有機鋰試劑反應, 可以避免二烷(芳)基硼烷和三烷(芳)基硼烷的產(chǎn)生。反應完后通常加入稀鹽酸酸化直接高收率地得到芳基硼酸酯 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.; Rangais

9、henvi, M. V. Tetrahedron Lett. 1990, 49, 7113, 7115.。2.1.1 通過Grinard試劑制備單取代芳基硼酸示例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 mag

10、netic 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 fil

11、led 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). T

12、he 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

13、mL, 14.5 g, 140 mmol). The mixture 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

14、 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.

15、 The resulting white solid is dissolved 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

16、. 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 通過有機鋰試劑制備單取代芳基硼酸示例 Chem. Eur. J. 2003, 9, 4430-4441nBuLi (1.6_ in hexane, 1 mL, 1.6 mmol) at - 78 under nitrogen was added to a solution of 4-(trimethylsilylethynyl

17、) 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, d

18、ried (MgSO4) and evaporated to obtain the crude 4-(trimethylsilylethynyl) phenylboronic acid that was used without further purification.2.2 通過二硼烷頻哪酯制備芳基硼酸酯對于分子中帶有酯基、氰基、硝基、羰基等官能團的芳香鹵代物來說, 無法通過有機金屬試劑來制備相應的芳基硼酸。 1995年由Ishiyama Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.率先取得了突破:

19、通過二硼烷頻哪酯和芳基鹵發(fā)生偶聯(lián)反應制備相應的芳基硼酸酯 (yield: 60-98%)。這個方法還有一個突出的優(yōu)點就是還可以原位制備硼酸酯, 然后“一鍋法”和芳基鹵反應用于芳基-芳基偶聯(lián)反應。在極性溶劑里此偶聯(lián)反應的產(chǎn)率可以得到很大的提高：DMSO DMF dioxane toluene。經(jīng)過驗證，KOAc是應用于這個反應最合適的堿，其他的如K3PO4或K2CO3這些堿性略強的堿會進一步使原料芳基鹵發(fā)生自偶聯(lián)反應的結果。對于制備溴代物和碘代物相應的芳基硼酸酯，Pd(dppf)Cl2一般可以得到很好的結果，又由于其具有易于反應的后處理的優(yōu)點，因此是公司目前最常用的一類催化劑。對于氯代物，200

20、1年Ishiyama經(jīng)過研究發(fā)現(xiàn)在 Pd(dba)2/2.4PCy3(3-6mol %) 的催化下此類反應可以接近當量的進行 Tatsuo Ishiyama, Tetrahedron 57 (2001) 9813-9816，下表是研究過程中對配體的遴選的情況：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

21、 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 on 4-chlorobenzaldeh

22、yde.c 1,1-Bis(diphenylphosphino)ferrocene.如Table 2所示，對一些有代表性的芳基氯進行硼酸酯化反應。對于含有吸電子集團的芳基氯，例如NO2、CN、CHO和CO2Me（Entry 1,3,5 and 6），反應進行的很快。而對于含有給電子集團(Entry 8-13)或有位阻影響的集團(Entry 2, 4)的芳基氯，反應就明顯緩慢下來，需要更長的時間和更多的催化劑來完成。例外的是，2-氯吡啶(Entry 15)不能得到目標產(chǎn)物。對這種氯原子緊鄰芳環(huán)雜原子的芳基氯進行反應的過程中，產(chǎn)生的硼酸或硼酸酯實在是太敏感了，很容易就轉變?yōu)殡s原子芳環(huán)，如吡啶。Ta

23、ble 2. Synthesis of pinacol arylboronatesEntryChloroareneMol%aTime (h)Yield (%)b14-O2NC6H4Cl348822-O2NC6H4Cl3487234-NCC6H4Cl349842-NCC6H4Cl3487254-OHCC6H4Cl369464-MeO2CC6H4Cl36877C6H5Cl6489184-MeC6H4Cl6489292-MeC6H4Cl34886104-MeOC6H4Cl64878113-MeOC6H4Cl64892122-MeOC6H4Cl34870134-Me2NC6H4Cl64873142-C

24、hloronaphthalene34877152-Chloropyridine3480163-Chloropyridine3488217348731834872a Mol% of catalyst.b GC yields based on chloroarenes.對于一些富電子的芳基氯化物和碘化物，用Pd(dppf)Cl2進行硼酸酯化的收率較低，而用Pd(dba)2/2.4PCy3(3-6mol %)在dioxone中會得到較好的結果，如下表所示：EDGX=Catalyst/solventTime/hYield%MeOIPdCl2(dppf)/DMSO282BrPdCl2(dppf)/DMS

25、O2469BrPd (dba) 2-PCy3/dioxane781OTfPdCl2(dppf)-dppf/dioxane1393OTfPd (dba) 2-PCy3/dioxane283Me2NIPdCl2(dppf)/DMSO690BrPdCl2(dppf)/DMSO2423BrPd (dba) 2-PCy3/dioxane681 2.2.1 通過二硼烷頻哪酯制備芳基硼酸酯示例（一）A flask charged with palladium catalyst (0.03 mmol), KOAc (294 mg, 3.0 mmol), and diboron (279 mg, 1.1 mmo

26、l) 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. 2.2.

27、2 通過二硼烷頻哪酯制備芳基硼酸酯示例（二）2.2.3 通過芳基硼酸轉化為芳基硼酸酯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 to provide the desired

28、 product of sufficient purity for subsequent use.2.3 烯基硼酸酯的制備 Brown, H. C.; Imai, T. Organometallics 1984, 3, 13921395.2.4 烷基硼酸酯的制備 Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458460.2-3-(tert-Butyldimethylsiloxy)-1,2-syn-dideuteriopropyl-2-cyclohexen-1-one (syn-7). Propene cis-2 (150 mg,

29、 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

30、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 separated and washed with 2 _ 25 mL of Et2O. The combined organic layers were dried over Na2SO4, filte

31、red, and reduced in vacuo. Purification by flash chromatography (10:90 EtOAc:hexane) yielded pure product as a colorless oil (119 mg, 51%).3 催化劑的制備3.1 Pd(PPh3)4的制備 A mixture of palladium dichloride (17.72 g., 0.10 mole), triphenylphosphine (131 g, 0.50 mole), and 1200 ml of dimethyl sulfoxide is pla

32、ced 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

33、 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 hypode

34、rmic 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

35、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 wei

36、ghs 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. Propert

37、ies: The Pd(PPh3)4 complex obtained by this procedure is a yellow, crystalline material 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

38、 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的制備將PdCl2 (50 g, 0.284 mol)和PPh3 (162.5 g, 0.62 mol) 加入苯腈（150 mL）中，氮氣置換三次，升溫到200，反應30 分鐘，降溫至室溫析出晶體，濾出固體，用乙醚洗滌，抽干，得到產(chǎn)品（362 g, 95.8 %）。3.3 Pd(dppf)Cl2的制備To absolute acetonitr

39、ile (1950 mL) degassed via 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 a

40、dded 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

41、complex can be recrystallized from chloroform/benzene.4 Suzuki偶聯(lián)的應用在整個suzuki-coupling反應循環(huán)中，Pd(0)與鹵代芳烴發(fā)生氧化-加成反應生成Pd(II) 的絡合物這一步被認為是起決定作用的步驟。底物鹵代芳烴中離去集團的相對活性有如下特征：I - Otf - Br - Cl -。芳基和烯基上若帶有集團，則吸電子集團對氧化-加成的促進作用要比給電子集團強。在Pd(II)）的絡合物的還原-消除得到偶聯(lián)產(chǎn)品的步驟中，相對的速率為：arylaryl alkylaryl n-propyln-propyl ethylethy

42、l methylmethyl應用于suzuki反應的催化劑最經(jīng)典的是Pd(PPh3)4，其它的有PdCl2、PdCl2(dppf)、Pd(OAc)2、Pd(PPh3)2Cl2和NiCl2(dppf) 等等，它們分別具有一些如后處理容易、空氣敏感度低等的特點，在具體的反應上有成熟的應用。有些反應還需要另外一些高催化活性的配體的參與，它們具有的共性就是電負性較強和空間位阻大。這是因為電負性較強的配體是有利于氧化加成反應；空間位阻大的配體有利于還原消除。開發(fā)高效價廉的新催化劑和配體是一個研究的方向。4.1 普通的芳鹵和芳基硼酸的Suzuki偶聯(lián)這一類反應是我們最常碰到的，所用的方法即為Suzuki偶

43、聯(lián)反應的普通操作： 在水的存在下，加入催化劑、堿和有機溶劑，加熱回流一段合理的時間完成反應，但反應體系必須全程嚴格控制在無氧的環(huán)境下。通常如果反應可行的話，這種方法所得的產(chǎn)率也是較高的。堿的話多用K2CO3，也有K3PO4、 Na2CO3、CsF、Cs2CO3、t-Bu-Na等等,一般不用NaHCO3。堿的強度對大位阻的2,4,6-三甲基硼酸的偶聯(lián)反應的影響次序是: Ba(OH)2 NaOH K3PO4 Na2CO3 NaHCO3。但是, 用弱堿往往比用強堿反應干凈一些溶劑體系一般用toluene/ EtOH / H2O, 也有CH3CN / H2O或dioxane / H2O。Table 3

44、是Suzuki反應的常用條件:Table 3 The general conditions for Suzuki coupling 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.EntrySolventsCatalystBaseTemperature1dioxanePd(PPh3)4

45、K2CO31202DMFPd(PPh3)4K3PO4803DME / H2OPd(PPh3)4Na2CO3refluxed4Toluene / H2O, MeOHPd(PPh3)4Na2CO3refluxed5DMF / H2OPd(dppf)Cl2Na2CO31206MeCN / H2OPd(PPh3)4Na2CO3refluxed4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 體系Suzuki偶聯(lián)反應示例 Patent; Takeda Chemical Industries, Ltd.; Publ.: US6518257 B1 (2003/02/11)Under an arg

46、on 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

47、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

48、a colorless solid.4.2 大位阻芳基硼酸參與Suzuki偶聯(lián)反應芳基硼酸的立體位阻對Suzuki偶聯(lián)反應的影響比芳基鹵的立體位阻對Suzuki偶聯(lián)反應的影響大得多。當芳基硼酸的鄰位是二取代物時, 反應的速率很慢, 收率很低。加入強堿水溶液如NaOH或Ba(OH)2, 以苯和DME為溶劑對反應有顯著的加速作用 a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207. b) Kelly, T. R.; Garcia, A.; Lang, F.; Walsh, J. J.; Bhaskar, K.V.; Boyd, M.

49、 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.。堿的強度對2,4,6-三甲基硼酸的偶聯(lián)反應的影響次序是: Ba(OH)2 NaOH K3PO4 Na2CO3 NaHCO3。但是, 用弱堿往往比用強堿反應干凈一些 Watanabe, T.; Miyaura, N

50、.; Suzuki, A. Synlett 1992, 207.。有時候可以將大位阻芳基硼酸轉化為硼酸酯，可以取得滿意的結果 J. Organomet. Chem. 2002, 653, 269.。4.3 含敏感功能團的芳基硼酸（酯）參與Suzuki偶聯(lián)反應2-醛基苯硼酸和2-碘甲苯在Na2CO3水溶液和DME中80反應, 目標化合物的收率只有39%. 提高收率的一個方法是: 使用相應的芳基硼酸酯代替芳基硼酸, 以無水K3PO4為堿, 用DMF作溶劑, 收率可以提高到89%6. 如果芳基硼酸或芳鹵本身帶有其它對水敏感的集團，如易水解的酯基（尤其是甲酯，乙酯活性還低些）、氰基等等，這時也可以應用

51、這種方法，實驗證明在無水的情況下，即使堿不溶解，很多的底物也可以進行Suzuki偶聯(lián)反應。相應的芳基硼酸酯的制備方法可參考前述有關章節(jié)。如果底物既帶著酯基又只能在有水存在下才能反應的，怎么辦？ 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里反應了，因為會發(fā)生酯交換反應，但只要把其中的EtOH換成MeOH即可解決這個問題。方法之二：先得到羧酸產(chǎn)物然后再酯化。例如 4.3.3所示操作:4.3.1 芳基硼酸頻哪酯和芳基鹵代物的Suzuki偶聯(lián)To a solution of 3.862 g of I and 3.401 g of II in 80 mL of

52、 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 resi

53、due 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 帶

54、著酯基底物的Suzuki偶聯(lián)反應示例（一） Patent; Augeri, David J.; Publ.: US2002/55631 A1 (2002/05/09)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

55、 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 ch

56、romatography on silica gel with 10percent ethyl acetate/hexanes to provide additional product. 4.3.3 帶著酯基底物的Suzuki偶聯(lián)反應示例（二） http:/www.rhodium.ws/chemistry/lysergic.hendrickson.htmlInto 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-dica