Suzuki 反应应用一览

小布丁lj9exvnf 2021-05-12

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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(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）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]:

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[1]。

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 flaskcontaining magnesium turnings (1.94 g, 80 mmol) is equipped with a rubber septum, a 20-mLpressure-equalizing dropping funnel fitted with a rubber septum, aTeflon-coated magnetic stirring bar, and a reflux condenser fitted with anargon 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 oilbath. The dropping funnel is filled with1-bromo-3,4,5-trifluorobenzene(8.36 mL, 14.8 g, 70.0 mmol) andca. 1 mL is added to the boiling reaction mixture. After reaction hascommenced, the oil bath is removed, and the remainder of the aryl bromide isadded 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, aflame-dried, 500-mL, single-necked, round-bottomed flask equipped with aTeflon-coated magnetic stirring bar, a rubber septum, and an argon inlet ischarged with dry tetrahydrofuran(THF, 50 mL) and trimethylborate (15.7 mL, 14.5 g, 140 mmol). Themixture is cooled to 0°C,and the ether solution of (3,4,5-trifluorophenyl)magnesiumbromide prepared above is introduced in one portion via adouble-ended needle. The reaction mixture is allowed to warm to roomtemperature, stirred for 1 hr, and then treated with 200 mL of saturated ammoniumchloride solution. The organic layer is separated and the aqueouslayer is extracted with three 100-mL portions of ethyl acetate. The combined organic layers are washed withbrine (100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure. The resulting white solid is dissolved in aminimal 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 standovernight and then filtered to afford pure (3,4,5-trifluorophenyl)boronicacid as white crystals. Further recrystallization of the motherliquor 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]

nBuLi (1.6_ in hexane, 1 mL, 1.6 mmol) at -78℃ under nitrogen was addedto 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 waswarmed to 25 ℃, stirred for 30 min, andquenched with dilute HCl solution. Themixture was extracted with EtOAc (20 mL), washed with water, dried (MgSO4) andevaporated to obtain the crude 4-(trimethylsilylethynyl) phenylboronic acidthat 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[1]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[1]，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%)

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（Entry1,3,5 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了，很容易就转变为杂原子芳环，如吡啶。

Table 2. Synthesis of pinacol arylboronates

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：

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 diboron (279 mg, 1.1 mmol) was flushed with nitrogen. DMSO (6 mL) and haloarene (1.0 mmol) were thenadded. After being stirred at 80 ℃ for an appropriateperiod, the product was extracted with benzene, washed with water, and driedover anhydrous magnesium sulfate. Kugelrohr distillation in vacuo gave thearylboronates.

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) intoluene (70 m) was refluxed in aDean-Stark apparatus for 16 hours and concentrated. The concentrate was triturated with diethylether and filtered to provide the desired product of sufficient purity forsubsequent use.

2.3 烯基硼酸酯的制备[6]

2.4 烷基硼酸酯的制备[7]

2-[3-(tert-Butyldimethylsiloxy)-1,2-syn-dideuteriopropyl]-2-cyclohexen-1-one(syn-7). Propene cis-2 (150 mg, 0.86 mmol) wasadded to a solution of 9-BBN (126 mg, 1.03 mmol) in THF (15 mL) at 0 °C. The reaction mixture was heated toreflux for 12 h. The mixture was cooledto 25 °C, and2-iodo-2-cyclohexene-1-one (229 mg, 1.03 mmol), Pd(dppf)Cl2 (14 mg, 0.017mmol), and NaOH (0.6 mL, 3 M,aqueous) were added sequentially. Themixture was again brought to reflux where it remained for 2 h. The reaction mixturewas partitioned between NaCl (75 mL, saturated aqueous) and Et2O (50 mL). Theaqueous phase was separated and washed with 2 _ 25 mL of Et2O. The combinedorganic layers were dried over Na2SO4, filtered, and reduced in vacuo. Purification by flash chromatography (10:90EtOAc: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-bottomed flask equipped with amagnetic stirring bar and a dual-outlet adapter. A rubber septum and a vacuum-nitrogen systemare connected to the outlets, The system is then placed under nitrogen withprovision made for pressure relief through a mercury bubbler. The yellow mixture is heated by means of anoil bath with stirring until complete solution occurs (ca. 140℃). The bath is then taken away, and the solutionis rapidly stirred for approximately 15

minutes. Hydrazinehydrate (20 g, 0.40 mole) is thenrapidly added over approximately 1 minute from a hypodermic syringe. A vigorous reaction takes place with evolutionof nitrogen. The dark solution is thenimmediately cooled with a water bath; crystallization begins to occur at ca. 125℃. At this point the mixture is allowed to coolwithout external cooling. After themixture has reached room temperature it is filtered under nitrogen on a coarse,sintered-glass funnel. The solid iswashed successively with two 50 ml. portions of ethanol and two 50 ml portionsof ether. The product is dried bypassing a slow stream of nitrogen through the funnel overnight. The resulting yellow crystalline productweighs 103.5-108.5 g.(90-94% yield).

A meltingpoint determination on a sample in a sealed capillary tube under nitrogen gavea decomposition point of 116℃(uncorrected). This compares with asimilar determination (115℃) performedon the product prepared by the method of Malatesta and Angoletta.

Properties:

The Pd(PPh3)4complex obtained by this procedure is a yellow, crystalline material possessingmoderate solubilities in benzene (50 g/L),methylene chloride, and chloroform. The compoundis less soluble in acetone, tetrahydrofuran and acetonitrile. Saturated hydrocarbon solvents give noevidence of solution. Although thecomplex may be handled in air, it is best stored under nitrogen to ensure itspurity.

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

To absolute acetonitrile (1950 mL) degassed via threevacuum/nitrogen ingress cycle was added dichloropalladium (13 g, 73 mmol), the mixture was refluxedat 90~100 °C overnight. Thereactant was concentrated to obtain Pd(CH₃CN)₂Cl₂asorange solid. To a suspension of Pd(CH₃CN)₂Cl₂(19 g, 73 mmol) inbenzene (680 mL) was added a solution of dppf (40.6 g, 73 mmol) in benzene (680 mL), the mixture wasstirred at rt overnight, the reddish brown precipitate formed was collected byfiltration, 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, thecomplex 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：

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。

Table3是Suzuki反应的常用条件:

4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O体系Suzuki偶联反应示例[9]

Under an argon atmosphere, p-dibromobenzene (9.99 g), 4-methoxyphenylboronic acid (2.03 g) and tetrakistriphenylphosphinepalladium (497 mg) were dissolved in dimethoxyethane (20 ml). A 2Maqueous sodium carbonate solution (20 ml) was added and the mixture was heatedunder reflux for 14 h. The reactionmixture was cooled to room temperature and the precipitated crystals werecollected by filtration. The obtainedcrystals were dissolved in ethyl acetate and insoluble materials were filteredoff. The solvent was evaporated and theobtained 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]。

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]。

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.

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。

4.3.1芳基硼酸频哪酯和芳基卤代物的Suzuki偶联

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 withstirring. The mixture was refluxed forseveral hours until the material was disaappeared. The reaction mixture was cooled to roomtemperature. The dioxane was removed by rotary evaporation. The residue was poured into water andextracted with CH2Cl2. The organic layerwas dried over MgSO4, filtered and the solvent was removed by rotaryevaporation. The product was isolated byflash 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]

A mixture of methyl 4-bromobenzoate (21.5 g, 100 mmol), 4-fluorophenylboronicacid (14.7 g, 105 mmol),Pd(dppf)Cl2, CH2Cl2(1.48 g,2.0 mmol), and 2MNa2CO3(100 ML) in toluene (200 ML) and was heated to reflux, stirred for 10hours, diluted with ethyl acetate (200 ML), washed with water (100 ML) andbrine (50 ML), dried (MgSO4), filtered, and concentrated.The concentrate wasrecrystallized from ethyl acetate/hexanes to provide the desired product. The mother liquor was concentrated andpurified by flash column chromatography on silica gel with 10percent ethylacetate/hexanes to provide additional product.

4.3.3带着酯基底物的Suzuki偶联反应示例（二）[14]

Into500 ml anhydrous toluene in a 1 liter round bottom flask equipped with stirringbar was bubbled in a stream of argon via a needle for 30 min. Pd(PPh₃)₄(0.878g, 0.75 mmol) and3-chloro-pyridine-2,5-dicarboxylic acid dimethyl ester (3.44g, 15.0 mmol) were added into this solvent and theresulting mixture was stirred at r.t. under argon for 1 hour. A solution ofindole-4-boronic acid (1.86g,11.5 mmol) in 50 ml EtOH and a solution of 2Maqueous Na₂CO₃ (11.5 ml) was added into the reactionmixture at r.t. under argon. The mixture was heated under argon with vigorousstirring at 105ｰC for 8 hours. The reaction mixture was cooled and brine (200 ml) wasadded. The organic layer was separated and aqueous layer extracted withadditional CH₂Cl₂ (2x100 ml). The combined organic layerwas dried over Na₂SO₄ and evaporation of thesolvent left a yellowish solid. Purification of the crude material through ashort 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 compoundsdue to ester exchange. This solid was dissolved in 500 ml EtOH and the solutionwas stirred overnight at r.t. in the presence of catalytic HCl in diethylether. 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].

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.

4.6烯基硼酸参与Suzuki偶联反应

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。

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。

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]

4.9 镍催化体系用于Suzuki偶联反应

SyunSatio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。