1 媒介

1.1 Suzuki回响的通式

在钯催化下，有机硼化合物与有机卤素化合物进行偶联回响，这就供应了一类常用和有效的合成碳-碳键化合物的方式，我们称之为Suzuki 偶联回响，或Suzuki-Miyaura 偶联回响。

Suzuki回响的通式

1.2 Suzuki回响的机理

Suzuki偶联回响的催化轮回过程平日认为先是Pd(0)与卤代芳烃发生氧化-加成回响生成Pd(II) 的络合物 1，然后与活化的硼酸发生金属转移回响生成Pd(II)）的络合物 2，最后进行还原-消弭而生成产品和Pd(0)。

1.3 Suzuki回响的特点及研究偏向

这类偶联回响有一些凸起的长处，好比：1.回响对水不敏感； 2. 可许可多种活性官能团存在；3. 能够进行平日的区域和立体选择性的回响，尤其是，这类回响的无机副产品是无毒的而且易于除去，这就使得其不光适用于实验室并且能够用于工业化生产。

其瑕玷是氯代物（稀奇是空间位阻大的氯代物）及一些杂环硼酸回响难以进行。

今朝，Suzuki 偶联回响的研究首要在以下几个方面：（1）合成并筛选可以在暖和的前提下高效催化卤代芳烃（稀奇是氯代芳烃）的配体；（2）多相催化系统的Suzuki偶联回响研究；（3）应用于Suzuki 偶联回响的新合成方式研究。

2 有机硼试剂的合成

2.1 经由金属有机试剂制备单庖代芳基硼酸

经典合成单庖代芳基硼酸(酯)的方式是用格氏试剂或锂试剂和硼酸酯回响来制备[1]:

用这种经典方式的瑕玷是单庖代芳基硼酸酯有进一步生成二庖代硼酸，甚至三烷基硼的或者，是以回响须在低温下进行。解决这个问题的一个有效的法子是使用硼酸三异丙酯和有机锂试剂回响, 能够避免二烷(芳)基硼烷和三烷(芳)基硼烷的发生。回响完后平日到场稀盐酸酸化直接高收率地获得芳基硼酸酯[1]。

2.1.1经由Grinard试剂制备单庖代芳基硼酸示例

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经由有机锂试剂制备单庖代芳基硼酸示例[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 经由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、羰基等官能团的芬芳卤代物来说, 无法经由有机金属试剂来制备响应的芳基硼酸。 1995年由Ishiyama[1]率先取得了冲破:  经由二硼烷频哪酯和芳基卤发生偶联回响制备响应的芳基硼酸酯 (yield: 60-98%)。这个方式还有一个凸起的长处就是还能够原位制备硼酸酯, 然后“一锅法”和芳基卤回响用于芳基-芳基偶联回响。

在极性溶剂里此偶联回响的产率能够获得很大的提高：DMSO≥DMF > dioxane> toluene。

经由验证，KOAc是应用于这个回响最合适的碱，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回响的究竟。

对于制备溴代物和碘代物响应的芳基硼酸酯，Pd(dppf)Cl₂一样能够获得很好的究竟，又因为其具有易于回响的后处理的长处，是以是公司今朝最常用的一类催化剂。

对于氯代物，2001年Ishiyama经由研究发现在 Pd(dba)₂/2.4PCy₃(3-6mol %) 的催化下此类回响能够接近当量的进行[1]，下表是研究过程中对配体的遴选的情形：

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回响。对于含有吸电子集体的芳基氯，例如NO₂、CN、CHO和CO₂Me（Entry1,3,5 and 6），回响进行的很快。而对于含有给电子集体(Entry 8-13)或有位阻影响的集体(Entry 2, 4)的芳基氯，回响就显着迟缓下来，需要更长的时间和更多的催化剂来完成。破例的是，2-氯吡啶(Entry 15)不克获得方针产品。对这种氯原子紧邻芳环杂原子的芳基氯进行回响的过程中，发生的硼酸或硼酸酯实在是太敏感了，很轻易就改变为杂原子芳环，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中会获得较好的究竟，如下表所示：

2.2.1经由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经由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) 到场苯腈（150 mL）中，氮气置换三次，升温到200℃，回响30 分钟，降温至室温析出晶体，滤出固体，用乙醚洗涤，抽干，获得产物（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)₂Cl₂ asorange 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回响轮回中，Pd(0)与卤代芳烃发生氧化-加成回响生成Pd(II) 的络合物这一步被认为是起决意感化的步伐。

底物卤代芳烃中离去集体的相对活性有如下特征：I ^- > Otf ^- > Br ^->> Cl ^-。

芳基和烯基上若带有集体，则吸电子集体对氧化-加成的促进感化要比给电子集体强。在Pd(II)）的络合物的还原-消弭获得偶联产物的步伐中，相对的速度为：

aryl–aryl > alkyl–aryl >n-propyl–n-propyl > ethyl–ethyl > methyl–methyl

应用于suzuki回响的催化剂最经典的是Pd(PPh₃)₄，另外的有PdCl₂、PdCl₂(dppf)、Pd(OAc)₂、Pd(PPh₃)₂Cl₂和NiCl₂(dppf) 等等，它们离别具有一些如后处理轻易、空气敏感度低等的特点，在具体的回响上有成熟的应用。有些回响还需要此外一些高催化活性的配体的介入，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回响；空间位阻大的配体有利于还原消弭。斥地高效价廉的新催化剂和配体是一个研究的偏向。

4.1 通俗的芳卤和芳基硼酸的Suzuki偶联

这一类回响是我们最常碰着的，所用的方式即为Suzuki偶联回响的通俗把持：在水的存鄙人，到场催化剂、碱和有机溶剂，加热回流一段合理的时间完成回响，但回响系统必需全程严厉掌握在无氧的情况下。平日若是回响可行的话，这种方式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,一样不消NaHCO₃。碱的强度对大位阻的2,4,6-三甲基硼酸的偶联回响的影响递次是: Ba(OH)₂>NaOH > K₃PO₄ > Na₂CO₃ >NaHCO₃。然则, 用弱碱往往比用强碱回响清洁一些

溶剂系统一样用toluene/ EtOH / H₂O, 也有CH₃CN / H₂O或dioxane / H₂O。

Table3是Suzuki回响的常用前提:

4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O系统Suzuki偶联回响示例[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 大位阻芳基硼酸介入Suzuki偶联回响

芳基硼酸的立体位阻对Suzuki偶联回响的影响比芳基卤的立体位阻对Suzuki偶联回响的影响大得多。当芳基硼酸的邻位是二庖代物时, 回响的速度很慢, 收率很低。到场强碱水溶液如NaOH或Ba(OH)₂, 以苯和DME为溶剂对回响有显著的加快感化[10]。碱的强度对2,4,6-三甲基硼酸的偶联回响的影响递次是: Ba(OH)₂>NaOH > K₃PO₄ > Na₂CO₃ >NaHCO₃。然则, 用弱碱往往比用强碱回响清洁一些[11]。

有时候能够将大位阻芳基硼酸转化为硼酸酯，能够取得写意的究竟[12]。

4.3 含敏感功能团的芳基硼酸（酯）介入Suzuki偶联回响

2-醛基苯硼酸和2-碘甲苯在Na₂CO₃水溶液和DME中80℃回响, 方针化合物的收率只有39%. 提高收率的一个方式是: 使用响应的芳基硼酸酯取代芳基硼酸, 以无水K₃PO₄为碱, 用DMF作溶剂, 收率能够提高到89%⁶. 

若是芳基硼酸或芳卤自己带有另外对水敏感的集体，如易水解的酯基（尤其是甲酯，乙酯活性还低些）、氰基等等，这时也能够应用这种方式，实验证实在无水的情形下，即使碱不消融，好多的底物也能够进行Suzuki偶联回响。响应的芳基硼酸酯的制备方式可参考前述有关章节。

若是底物既带着酯基又只能在有水存鄙人才能回响的，怎么办？方式之一：到场痕量的水, 若是底物自己含有甲酯就不克在toluene/EtOH/H2O里回响了，因为会发生酯交流回响，但只要把个中的EtOH换成MeOH即可解决这个问题。方式之二：先获得羧酸产品然后再酯化。

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偶联回响示例（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偶联回响示例（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 杂环芳基硼酸介入Suzuki偶联回响

杂环芳基硼酸参与Suzuki偶联回响同样能够获得好的究竟[15].

4.5烷基硼酸介入Suzuki偶联回响

对于芳基卤和甲基硼酸(酯)介入的Suzuki回响, 收率一样都很低。一个改善的方式是用剧毒的TlOH或Tl₂CO₃作碱, Suzuki回响的收率有提高[17]。最近有报道用甲基三氟硼酸钾取代甲基硼酸, 取得了较好的究竟。这种方式凸起的长处是试剂易于制备, 对空气不乱, 而且用于Suzuki偶联回响一样能够获得较好的究竟.

4.6烯基硼酸介入Suzuki偶联回响

4.7 Triflate介入Suzuki偶联回响

因为三氟甲基磺酸酯能够由响应的酚或许酮轻易地制备, 这个试剂介入Suzuki偶联回响吸引了越来越多的科学研究者的乐趣。

三氟甲基磺酸酯和芳基硼酸的偶联回响有时候会因为在回响初期, 催化剂配体PPh₃轻易和triflate回响, 从而导致催化剂分化损坏为钯黑。若是在回响系统中到场和催化剂等当量的LiBr 或KBr就足以阻止这种分化回响。

4.8 芳基氯介入Suzuki偶联回响

Mitchell等报导了用dppb作钯的配体，可以有效地催化氯代芳杂类同芳基硼酸进行Suzuki回响，产率高达98%; 之后Wang Shen等用三环已基磷(PCy₃)作钯的配体，发现此配体催化剂可以最有效地激活芳氯键，这或者是因为三环已基磷比三苯基磷有更多的电子，因而能够增加钯氧化插入芳氯键的能力，同时还发如今Pd(PCy₃)Cl₂催化下，邻对位吸电子庖代芳基氯能更有效的进行回响。

4.8.1钯催化下芳基氯介入Suzuki偶联回响示例（一）[21]

4.9 镍催化系统用于Suzuki偶联回响

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回响，零价镍自NiCl₂(dppf) （10 mol%）和n-BuLi(40 mol%)“一锅”回响来制备，而氯代芳烃可带有各类吸电子或给电子基因. 此方式中镍催化剂成本低，同时选用廉价的氯代芳烃作为回响物，因而有很高的工业应用价格；也有人研究使用NiCl₂(PPh₃)₂来催化烷基庖代硼酸盐和溴代物的偶取回响，在室温下以80%的高产率合成了生物活性化合物。

4.9.1NiCl₂(dppf)和n-BuLi催化下芳基氯介入Suzuki偶联回响示例[23]

4.10 其他方式

研究发现，对某些碘代物，一些无磷配体催化剂能够在较为暖和的前提下高效的催化回响，如PdCl₂、Pd(OAc)₂、Pd/C等。同时，也能够避免回响中配体所形成的杂质对产物星散过程发生的困扰。

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