Suzuki反应-药明康德

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药明康德合成

DPPA(diarylphosphoryl azide)作为叠氮基团的来源, 可以更方便地将羟基转变成叠氮基
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Mitsunobu 氨基取代反应
磺酰肼与α--羟基取代炔经过Mitsunobu氨基取代反应，生成的产物不稳定，马上分解为丙二烯化合物，这是一个制备丙二烯化合物的比较便捷的方法
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Mitsunobu 硫代反应
R'COOH
O
R OH DEAD, PPh3 R O R'
Mitsunobu
K2CO3 MeOH
R OH
R'COOH: AcOH, O2N
COOH
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Mitsunobu应用, 手性醇的翻转
最早将Mitsunobu 手性翻转用于天然产物的合成，只需一步就将5α-choletan-3β-ol 转变为5α-choletan-3α-ol
这类偶联反应有一些突出的优点：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向：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。
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Mitsunobu醇的翻转---应用
p-硝基苯甲酸（PNBA）作为亲核试剂对立体位阻较大的醇的翻转更有效
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Mitsunobu 分子内环化
分子内的Mitsunobu反应为内酯的合成提供一个有效的方法

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目录1 前言 (3)1.1 Suzuki反应的通式 (3)1.2 Suzuki反应的机理 (3)1.3 Suzuki反应的特点及研究方向 (4)2 有机硼试剂的合成 (4)2.1 通过金属有机试剂制备单取代芳基硼酸 (4)2.1.1 通过Grinard试剂制备单取代芳基硼酸示例 (4)2.1.2 通过有机锂试剂制备单取代芳基硼酸示例 (5)2.2 通过二硼烷频哪酯制备芳基硼酸酯 (6)2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一） (9)2.2.2 通过二硼烷频哪酯制备芳基硼酸酯示例（二） (10)2.2.3 通过芳基硼酸转化为芳基硼酸酯 (10)2.3 烯基硼酸酯的制备 (10)2.4 烷基硼酸酯的制备 (10)3 催化剂的制备 (11)3.1 Pd(PPh3)4的制备 (11)3.2 Pd(PPh3)2Cl2的制备 (12)3.3 Pd(dppf)Cl2的制备 (12)4Suzuki偶联的应用 (12)4.1 普通的芳卤和芳基硼酸的Suzuki偶联 (13)4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例 (14)4.2 大位阻芳基硼酸参与Suzuki偶联反应 (14)4.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应 (15)4.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联 (16)4.3.2 带着酯基底物的Suzuki偶联反应示例（一） (16)4.3.3 带着酯基底物的Suzuki偶联反应示例（二） (17)4.4 杂环芳基硼酸参与Suzuki偶联反应 (17)4.5烷基硼酸参与Suzuki偶联反应 (18)4.6烯基硼酸参与Suzuki偶联反应 (19)4.7 Triflate参与Suzuki偶联反应 (19)4.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例 (20)4.7.2 芳基的Triflate与芳基硼酸偶联示例 (20)4.8 芳基氯参与Suzuki偶联反应 (21)4.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一） (21)4.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二） (22)4.9 镍催化体系用于Suzuki偶联反应 (22)4.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例 (22)4.10 其他方法 (23)4.10.1 直接Pd/C用于Suzuki偶联反应示例 (23)4.10.2 直接Pd(OAc)2用于Suzuki偶联反应示例 (23)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。

吡啶类硼酸的制备

含氮杂环硼酸的制备及研究罗彤硼酸是有机合成中一种比较重要的试剂。

硼酸与芳基卤代物在零价钯催化下，同过耦合反应生成二苯基类化合物。

同样Suzuki coupling reaction 在不对成合成二苯基类化合物及其衍生物时也是非常好的方法，当使用有机锂试剂，有机镁试剂以及其它有机金属试剂进行Suzuki coupling reaction时，反应化合物的官能团，稳定性以及毒性等性质方面都居有广泛的选择性。

近期在许多重要的药物研发过程中（蛋白质抑制），硼酸的使用已经的到很大的发展，因而硼酸在高通量新颖化合物的合成过程中的应用得到加强。

另外，硼酸作为金属催化耦合反应中的固态连接体在固相合成中的应用研究也取得不错的成绩。

在Suzuki coupling reaction中，使用杂环卤代物和苯硼酸进行反应的报道已经非常之多, 而且采用有机镁试剂，锌试剂，锡试剂等方法也常有报道。

与之相比，采用杂环硼酸与芳基卤代物的反应却报到的很少。

因此，杂环硼酸的制备与应用依然是一个有机合成中的热点。

含氮杂环化合物有很多，通常有吡啶，吡咯，吲哚，咪唑，喹啉以及嘧啶这些类化合物。

1.吡啶硼酸类1.1 2-吡啶硼酸：2-吡啶硼酸的合成现在依然存在一些难点。

如（Scheme 1）,我们虽然可以成功的分离得到锂硼盐1，但是一旦该锂盐遇到质子性溶剂的时候。

它将很快地分解成为吡啶和硼酸。

N Br 1.BuLi2.B(OBa)Protic solventNB(OH)3N BrHB OHEt2Heat to180℃N BEt223Scheme 1与不稳定的化合物1相比，化合物2以及加热其所生成的化合物3都是稳定的化合物。

化合物3以及其的二聚物稳定性可以通过B-N 键的键长以及硼分子的四面体结构来解释。

从反应的机理上来说，同样的硼酸二乙酯也可视为硼酸在Suzuki coupling reaction 中得到应用，因此对于2-吡啶硼酸来说，采用2-吡啶硼酸酯是比较可行的办法。

Suzuki反应

铃木反应维基百科，自由的百科全书（重定向自Suzuki反应）Suzuki反应（铃木反应），也称作Suzuki偶联反应、Suzuki-Miyaura反应（铃木－宫浦反应），是一个较新的有机偶联反应，是在钯配合物催化下，芳基或烯基的硼酸或硼酸酯与氯、溴、碘代芳烃或烯烃发生交叉偶联。

[1][2]该反应由铃木章在1979年首先报道，在有机合成中的用途很广，具有很强的底物适应性及官能团耐受性，常用于合成多烯烃、苯乙烯和联苯的衍生物，从而应用于众多天然产物、有机材料的合成中。

[3][4][5]。

铃木章也凭借此贡献与理查德·赫克、根岸英一共同获得2010年诺贝尔化学奖。

[6]目录[隐藏]∙ 1 概述∙ 2 机理∙ 3 讨论∙ 4 展望∙ 5 参见∙ 6 参考文献∙7 外部链接[编辑]概述Suzuki反应对官能团的耐受性非常好，反应物可以带着-CHO、-COCH3、-COOC2H5、-OCH3、-CN、-NO2、-F等官能团进行反应而不受影响。

反应有选择性，不同卤素、以及不同位置的相同卤素进行反应的活性可能有差别，三氟甲磺酸酯、重氮盐、碘鎓盐或芳基锍盐和芳基硼酸也可以进行反应，活性顺序如下：R2-I > R2-OTf > R2-Br >> R2-Cl另一个广泛应用的底物是芳基硼酸，由芳基锂或格氏试剂与烷基硼酸酯反应制备（见Miyaura硼酸化反应，Miyaura反应)。

这些化合物对空气和水蒸气比较稳定，容易储存。

Suzuki反应靠一个四配位的钯催化剂催化，广泛使用的催化剂为四(三苯基膦)钯(0)Pd(PPh3)4与PdCl2(dppf)，其他的配体还有：AsPh3、n-Bu3P、(MeO)3P，以及双齿配体Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp)等。

（以上的所有Pd配体都是厌氧的，因此反应必须在氮气，氩气等惰性气体下反应）。

[7]Suzuki反应中的碱也有很多选择，最常用的是碳酸钠，碳酸铯，醋酸钾，磷酸钾等。

suzuki反应脱硼副产物

suzuki反应脱硼副产物摘要：一、引言二、Suzuki 反应的简介三、Suzuki 反应中的脱硼副产物四、脱硼副产物的影响和应对策略五、结论正文：一、引言Suzuki 反应是一种在有机合成中广泛应用的偶联反应，由日本化学家Akira Suzuki 教授在1979 年首次报道。

该反应以其高度的立体选择性和区域选择性而受到研究者们的青睐，然而在实际应用过程中，反应中可能产生的脱硼副产物成为一个值得关注的问题。

二、Suzuki 反应的简介Suzuki 反应是一种钯催化的偶联反应，通过使用钯催化剂和卤代芳烃与有机硼化合物进行反应，生成新的化学键。

该反应的特点是条件温和、反应速度快、产率高，并且具有很好的立体选择性和区域选择性。

这使得Suzuki 反应在有机合成领域具有广泛的应用前景。

三、Suzuki 反应中的脱硼副产物在Suzuki 反应过程中，虽然钯催化剂具有很高的选择性，但仍然可能产生脱硼副产物。

脱硼副产物通常是由于反应过程中有机硼化合物的结构发生改变而产生的，这可能影响反应的产率和立体选择性。

脱硼副产物的生成与有机硼化合物的结构、反应条件和催化剂的种类等因素密切相关。

四、脱硼副产物的影响和应对策略脱硼副产物的生成可能对反应产率和立体选择性产生负面影响。

为了提高Suzuki 反应的效果，研究者们采取了一系列策略来减少脱硼副产物的生成，如优化反应条件、选择合适的有机硼化合物、使用高活性的钯催化剂等。

此外，对反应过程中产生的脱硼副产物进行及时监测和处理，也有助于提高反应的效果。

五、结论Suzuki 反应是一种在有机合成中具有广泛应用的偶联反应，然而反应过程中可能产生的脱硼副产物对其产率和立体选择性产生影响。

经典合成反应标准操作药明康德目录

经典化学合成反应标准操作药明康德新药开发有限公司化学合成部编写前言有机合成研究人员在做化学反应经常碰到常规的反应手边没有现成的标准操作步骤而要去查文献，在试同一类反应时，为了寻找各种反应条件方法也得去查资料。

为了提高大家的工作效率，因此化学合成部需要一份《经典合成反应标准操作》。

在这份材料中，我们精选药物化学中各类经典的合成反应，每类反应有什么方法，并通过实际经验对每类反应的各种条件进行点评，供大家在摸索合成条件时进行比较。

同时每种反应的标准操作，均可作为模板套用于书写客户的final report，这样可以大大节省研究人员书写final report的时间，也相应减少在报告中的文法错误。

另外本版是初版，在今后的工作中我们将根据需要修订这份材料。

药明康德新药开发有限公司化学合成部2005-6-28目录1.胺的合成a)还原胺化b)直接烷基化c)腈的还原d)酰胺的还原e)硝基的还原f)叠氮的还原g)Hoffman降解h)羧酸通过Cris 重排2.羧酸衍生物的合成a)酰胺化的反应b)酯化反应c)腈转化为酯和酰胺d)钯催化的插羰反应e)酯交换为酰氨3.羧酸的合成a)醇氧化b)酯水解c)酰胺的水解d)腈的水解e)有机金属试剂的羰基化反应f)芳香甲基的氧化4.醛酮的合成a)Weinreb 酰胺合成醛酮b)醇氧化c)酯的直接还原d)有机金属试剂对腈加成合成酮5.脂肪卤代物的合成a)醇转化为脂肪溴代物通过PBr3 转化通过PPh3 与CBr4 转化HBr直接交换通过相应的氯代物或磺酸酯与LiBr交换、b)醇转化为脂肪氯代物通过SOCl2转化通过PPh3 与CCl4 转化HCl直接交换c)醇转化为脂肪碘代物通过PPh3 与I2 转化通过相应的氯代物或磺酸酯与NaI交换6.芳香卤代物的合成a)Sandermyyer 重氮化卤代b)直接卤代c)杂环的酚羟基或醚的卤代7.醇的合成a)羧酸或酯的还原b)醛酮的还原c)卤代烃的水解d)吡啶的氧化转位8.酚的合成a)Sandermayer 重氮化反应b)醚的水解c)Bayer-vigerlar 氧化d)硼酸的氧化9.腈的合成a)磺酸酯或卤代烃的取代b)酰胺的脱水c)芳卤代烃的氰基取代10.硝化反应11.醚的合成a)芳香醚的合成酚与烷基卤代烃的直接烷基化Mitsunobu 芳香醚化Buckwald芳香醚化b)脂肪醚的合成醇的醚化12.脲的合成a)胺与异腈酸酯的反应b)用三光气合成脲c)羰基二咪唑（CDI）合成脲d)对硝基苯酚碳酰胺合成脲13.烯烃的合成a)Wittig 反应b)羟基的消除c)Wittig-Horner 反应合成α,β-不饱和酯14.磺酸及磺酰氯的合成a)氯磺化反应合成磺酰氯b)从硫醇合成磺酰氯c)磺化反应15.氨基酸的合成a)Streck 反应合成b)手性氨基酸的合成16.偶联反应a)Suzuki Couplingb)Buckwald 芳胺化，芳酰胺化、c)Heck 反应17.Mitsunobu 反应a)醇的反转b)胺的取代18.脱羟基反应19.酮还原为亚甲基20.氨的保护及脱保护策略a)用碳酰胺作保护基b)苄基保护21.醇的保护及脱保护策略a)用硅醚进行保护b)其他醚类保护22.羧基的保护格氏反应---------------------------------------------------------------------------------------------------------1还原胺化---------------------------------------------------------------------------------------------------------2卤化反应---------------------------------------------------------------------------------------------------------2 Suzuki coupling-------------------------------------------------------------------------------------------------2磺化反应---------------------------------------------------------------------------------------------------------3酯化反应---------------------------------------------------------------------------------------------------------3水解反应---------------------------------------------------------------------------------------------------------3硝化反应---------------------------------------------------------------------------------------------------------4 n-BuLi------------------------------------------------------------------------------------------------------------4 LiAlH4还原-----------------------------------------------------------------------------------------------------4 POCl3的杂环氯代----------------------------------------------------------------------------------------------5 NaH---------------------------------------------------------------------------------------------------------------5 NBS---------------------------------------------------------------------------------------------------------------5m-CPBA ----------------------------------------------------------------------------------------------------------6EDC ---------------------------------------------------------------------------------------------------------------6用三光气成脲---------------------------------------------------------------------------------------------------7芳卤用n-BuLi 处理后与Weinreb 酰胺成酮-----------------------------------------------------------------7Boc 上保护OHH 2NHO OOOOOO OHN HO OHO O ABTo a solution of A (2.72 g, 13.9 mmol) and tetramethylammonium hydroxide pentahydrate (5.62 g, 31.0 mmol) in acetonitrile (270 mL) was added di-tert-butyldicarbonate (3.79 g; 17.4 mmol) and the resulting solution was allowed to stir 18 h at rt and concentrated. The residue was partitioned between Et2O/H2O; the phases were separated and the aqueous phase extracted twice more with Et2O. The aqueous phase was brought to pH 4 with solid citric acid and extracted with CHCl3 (3.x.100 mL). The organic extracts were combined, dried (Na2SO4) and concentrated to afford 2.58 g (63 percent) B as a white foam.ReturnBoc 脱保护OON HOOOOH 2NTert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8 g, 89 mmol) in dichloromethane (10 ml) was cooled to 0 deg C and stirred as a mixture of trifluoroacetic acid: dichloromethane (1:1, 40 ml) was added dropwise. The mixture was allowed to warm to rt, stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3*20 ml) and aqueous sodium hydroxide (10percent, 3*20 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphenoxy)ethylamine (13 g, 88percent yield) as a light yellow solid.Return格氏反应NCNNOA stirred mixture of magnesium turnings (23.6 g, 0.98 mol) and Et2O (200 mL) under nitrogen is treated with a crystal of iodine and about 5percent of a solution of bromoethane (56.3 ml, 0.75 mol) in Et2O (375 mL). When the reaction starts, the remainder of the bromoethane solution is added, dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring is continued for 1 hour. To this solution of ethylmagnesium bromide was slowly added a solution of 4-cyanopyridine (39 g, 0.375 mol) in Et2O (750 ml). The reaction mixture was warmed at reflux for 12 hours, treated with concentrated H2SO4 (125 ml)/H2O (125 ml), and then washed three times with Et2O (250 ml). The aqueous portion was made basic (PH 9) with 15percent NaOH solution and extracted five times with 250 ml portions of Et2O. The combined Et2O extracts were dried (MgSO4), and the solvent was removed under reduced pressure to afford a brown oil (48.4 g, 95percent).Return还原胺化OHO H 2N+HON HA solution of 2-amino-4-ethylphenol (1.00 g. 7.28 mmol), 2-naphthaldehyde (1.13 g, 7.28 mmol), andp-toluenesulfonic acid (0.05 g) in methanol (50 ML) was stirred at room temp for 24 h. To the resultant solution, sodium borohydride (0.82 g, 22 mmol) was added in small portions. After addition was completed, the mixture was stirred at room temperature for 30 min and concentrated under vacuum. The residue was then subjected to column chromatography on silica gel eluted with 10percent ethyl acetate in hexane and followed by recrystallization (aqueous methanol) yielded 450 mg (22percent) of analytically pure product.Return卤化反应O2N O2NBrTo a stirred solution of 8-methyl-1-nitro-naphthalene (10.6g, 56.32 mmol) and iron (III) chloride (0.45 g, 2.77 mmo) in CCl4 (150 ml) heated to 60°C was added dropwise (3.0 ml, 58.23 mmol) of bromine. After one hour, the reaction mixture was poured into saturated NaHCO3 solution, and the layers were separated. The aqueous layer was re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was recrystallized from ethanol and the mother liquors were concentrated and then flash chromatographed on silica, eluding hexanes:ethyl acetate (12: 1).ReturnSuzuki couplingBrBOO NH+NH To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mnmol) and3-bromobenzene (0.87 ml, 8.3 mmol) in THF (28 ml) were added palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 ml of water).The system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70 °Coil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluding with hexanes: EtOAc 9:1 to give 1.38 g (78%yield) of 4-phenyl-1H-indole as a colorless liquid.Return磺化反应NOFFFNOFFFSOClOChlorosulfonic acid (4.66g, 40 mmol) is added dropwise to a cold (0°C) solution of2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (2.9g, 8 mmol) in chloroform (800 ml). The resulting solution is stirred at 0°C for 30 minutes. The cold bath is then removed and the solution is stirred at room temperature for 1 hour then cautiously poured into ice water. The organic layer is separated, dried over magnesium sulfate and concentrated to afford the title compound. The crude product is purified by column chromatography eluted with 10% acetic ether in petroleum ether (2.36 g, 81% yield).Return酯化反应HOHO O HOO OA mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 ml), and concentrate H2SO4(2 ml) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO3 (2*), brine, dried over MgSO4, and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%yield).Return水解反应OO OHOA solution of 1-Methyl-naphthalene-2-carboxylic acid methyl ester (7.20g, 35mmol) and 2N sodium hydroxide (35ml) in tetrahydrofuran (130ml) was stirred under reflux for 18 hours. The mixture was neutralised using 2N hydrochloric acid, and extracted with dichloromethane (3x). The combined organic solutions were dried (MgSO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gelusing an elution gradient of dichloromethane: methanol (100:0 to 97:3) to afford the title compound as a solid (3.11g, 47.8%yield).Return硝化反应NO 2To a cold (0°C) suspension of 1-methylnaphthalene (5 g, 35.2 mmol) in HNO3 was added H2SO4 (5 ml) dropwise. After stirring the reaction for one hour, the solution was diluted with ethyl acetate and washed with water (3*), aqueous saturated NaHCO3 (2*) and brine, dried over MgSO4, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate: hexane (5: 95) and recrystallized from methanol to give yellow needles (0.22g, 33% yield).Returnn-BuLiEtOCF 3O CF 3O NCTo a dry three-necked round-bottomed flask with an addition funnel and at -78°C under inert atmosphere was charged with anhydrous THF (500 ml). A solution of n-butyllithium (2.5 M in hexane, 88ml, 220 mmol) was added dropwise followed by addition of a solution of acetonitrile (10.43 ml, 200 mmol) in anhydrous THF (100 ml). The internal temperature was maintained below -70°C during the entire addition process. After 2 hr at -78°C a solution of Trifluoro-acetic acid ethyl ester (14.2 g, 100 mmol) in anhydrous THF (30 ml) was added dropwise and the mixture was stirred for 1.5 hr. To the mixture was added acetic anhydride to quench the reaction. The reaction mixture was allowed to warm up to rt. A precipitate was filtered and the filtrate was concentrated to give a brown oil, which was used in the next step without purification.ReturnLiAlH4还原HOHO O OHOHOA solution of 2,3-naphthalenedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 ml, warmed to 50° to maintain solution) is added dropwise over 15 minutes to a 1.15 M lithium aluminum hydride solution in THF (45 ml, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully with THF-water, then 2N hydrochloric acid (40 ml) is added, and the resulting mixture is extracted 3 times with ether. The combined ether extracts are washed with water (2 times), with saturated sodium bicarbonate solution (1 time), with water, and are dried (sodium sulfate), filtered, and concentrated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g, 67.3%yield) as a light tan crystalline material.ReturnPOCl3的杂环氯代NN HOOHN NClClTo a suspension of 2,4-dihydroxy-5,6-dimethylpyrimidine (6.2 g, 0.044 mol) in POCl3 (25 ml) was slowly added N,N-dimethylaniline (6.18 ml, 0.049 mol). The mixture was then refluxed at 125 °C for 3 hours. After this time, the starting material completely dissolved indicating that the reaction was completed.The reaction mixture was cooled and then poured slowly onto ice to quench the POCl3(caution[exothermic]). A precipitate formed, which was filtered and washed with ice-cold water. The precipitate was dried under high vacuum overnight to yield 2,4-dichloro-5,6-dimethyl-pyrimidine (7.2 g, 0.041 mol, 92%yield) as a yellow solid.ReturnNaHHSH 2N Cl +SNH 2Sodium hydride (50% in mineral oil, 5.5 g, 0.11 mol) was added portionwise at 0 °C under a nitrogen atmosphere to a solution of 2-aminobenzenethiol (12 ml, 0.1 mol) in DMF (120 ml). After 0.5 h, benzyl chloride (11.5 ml, 0.1 mol) in DMF (80 ml) was added in 0.5 h. The solution was stirred for 3 h while the temperature was allowed to rise to rt, then it was poured into ice/water (1000 g). The precipitate was filtered, dissolved in ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and evaporated. The solid obtained was ground in pentane (19.3 g, 90% yield).ReturnNBSNN FCl ClNBSN N FCl ClBrA mixture of 2,4-Dichloro-6-ethyl-5-fluoro-pyrimidine (27.46 g ， 0.14mol), AIBN (1.32 g) and n-bromosuccinimide (27.02 g ， 0.152mol) in CH2Cl2 (170 ml) was refluxed under a nitrogen atmosphere for 36 h. Then washed by water, the aqueous was extracted by CH2Cl2. The combined organic layer was washed by saturated Na2S2O3 and brine, dried over Na2SO4, and evaporated to give a white solid which was purified by column chromatography eluted with 50% acetic ether in petroleum ether (34 g, 88.6% yield).Return氢化反应O ONH OONH2Cl ClA mixture of ethyl 3-(N-benzylamino)-3-methylbutyrate hydrochloride (25g, 0.1 mol) and 10percent Pd-C (2g) in 250 ml of dried alcohol was hydrogenated under 55 psi H2 for four days. The reaction medium was then filtered and evaporated under reduced pressure to provide an amber oil which gradually crystallized upon standing (18 g, 100% yield).Returnm-CPBAS NH2SNH2OA solution of 85% m-chloroperoxybenzoic acid (19 g, 94 mmol) in CH2Cl2 (350 ml)was added at –5 –0 °C to a solution of 2-Benzylsulfanyl-phenylamine (19 g, 88 mmol) in CH2Cl2 (400 ml). The mixture was allowed to warm to rt in 3 h, then it was washed with a 5% Na2S2O3 solution, 10% NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and evaporated. The solid was ground in pentane (19 g, 95% yield).ReturnEDCNH2OHNOO+HOHOHNOOTo a 0°C mixture of Boc-L-tyrosine (2.04 g, 7.26 mmol) and amylamine (0.63 gl, 7.26 mmol) in methylene chloride (30 ml) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (1.53 g, 9.9 mmol). Thewhite mixture is stirred at 0°C for 5 min and at room temp for 23 hrs. The resulting solution is diluted with methylene chloride (30 ml) and washed successively with 0.5 M HCl (40 ml), water (20 ml) and sat aq sodium bicarbonate (25 ml). The organic phase is dried over magnesium sulfate and concentrated to a foam (1.84 g, 72.4%yield), sufficiently pure to carry into the next step. An analytical sample is obtained by HPLC.Return三光气成脲NH 2ONO 2Si O Cl Cl ClO O Cl Cl ClO 2NHN H NO OHOHNO 2+To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) in toluene (10 ml) triethylamine (0.13 ml, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. The reaction mixture was stirred at 70 °C for 2 hours, then cooled to room temperature. Then more 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70 °C for 48 hours then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane: ethyl acetate, 10:1) gave 1,3-Bis-(2-hydroxy-4-nitro-phenyl)-urea (130 mg, 31%yield).Return芳卤用n-BuLi处理后与Weinreb酰胺成酮N FFFFNOO+FFFO NFTo a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at –78°C under argon was added n-butyllithium (54.0 ml, 2.5M in hexane, 0.135 mole), followed after 5 min by dropwise a solution of 2-fluoro-4-methylpyridine (10 g, 0.090 mole) in THF (20 ml). After stirring for 15 min at –78°C, a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 ml) was added dropwise. After stirring for more 5 min, the reaction was allowed to warm to 0°C and quenched by pouring into water (400 ml) and ethyl acetate (400 ml). The layers were separated, and the aqueous layer washed with ethyl acetate (200 ml). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20percent ethyl acetate in hexane to give 21.6 g of 2-(2-Fluoro-pyridin-4-yl)-1-(3-trifluoromethyl-phenyl)-ethanone (84.8%yield).Return。

药明康德Pd催化的偶联反应MA070818精品PPT课件

在钯催化下，有机硼化合物与有机卤素化合物进行的偶联反应，称之为Suzuki偶联反应，或Suzuki-Miyaura 偶联反应。
R1 BY2
+
R2 X
[P d ] base
R1 R2
BY2 = B(OR)2, 9-BBN, B(CHCH3CH(CH3)2) X = I, Br, Cl, OSO2(CnF2n+1), n = 0,1,4
合成反应讲座(五)
Pd催化的偶联反应
化学合成部执行主任:
药明康德版权所有
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内容简介
Pd 催化的偶联反应有较多类型，目前用途最广泛的主要有以下三类:
1. Suzuki 反应 2. Heck 反应 3. Sonogashira 反应
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第一部分： Suzuki 反应
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1. 前言
1.1 Suzuki反应的通式
TMS 1.nBuLi,THF -78oC, 15min
TMS
2. B(OMe)3
I
-78oC-25oC,30min (HO)2B
3. H+/HCl
Chem. Eur. J. 2003, 9, 4430-4441
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2. 有机硼试剂的合成
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。
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1. 前言

Suzuki反应综述

Suzuki反应综述一、水溶性非膦配体/钯催化体系Wu 等以水溶性联吡啶基季铵盐为配体 19 (Scheme 14)用于Pd 催化的水相 Suzuki 反应. 在催化剂用量0.1 mol%, 芳基溴代物∶苯硼酸∶K 2CO3 ＝1 ∶1.3∶2( 物质的量比), 反应温度 100 ℃时, 取得较好的产物收率, 催化剂可循环利用5 次. 进一步研究发现 , 在TBAB 存在下, 此催化体系可有效实现芳基氯代物的偶联反应.Pawar 等将吡啶基二乙胺磺酸钠 20 (Scheme 15)作为配体和碱用于纯水相 Pd催化 Suzuki 反应. PdCl2 用量为5 mol%, 芳基卤代物∶芳基硼酸∶20＝1∶1.2∶1 ( 物质的量比), 室温条件下反应3 ～4 h, 可使芳基溴代物和芳基碘代物的Suzuki 反应较好进行.Adidou 等合成了一种键合在 PEG350 上的二吡啶基甲胺配体21 (Scheme 16), 成功用在纯水体系中 Pd催化的芳基氯代物 Suzuki 反应. Pd(OAc)2 用量为 0.1 mol%, 芳基氯代物∶芳基硼酸∶K 2CO3TBAB ＝1 ∶1.1∶2 ∶0.5( 物质的量比), 反应体系加热至100 ℃反应15 h, 取得较好的收率.Mai 等合成了一种与 PEG2000键合的二吡啶配体22 (Scheme 17), 成功用于芳基卤代物和四苯基硼酸钠的Suzuki 偶联反应(Eq.4)在PEG2000/H2O 的混合溶液中, Pd(OAc)2 用量为0.5 mol%, 反应温度 110 ℃时, 对芳基溴代物表现出较好的反应活性, 对于含吸电子基团的芳基氯代物也具有一定的反应活性.Zhou等合成系列二亚胺型配体 23 (Scheme 18),并成功用于水相Suzuki 反应. 在钯催化剂用量为 0.01 mol%, 芳基溴代物∶苯硼酸∶K 2CO3 ＝1 ∶1.3∶2( 物质的量比), 分别考察了水/ 乙醇混合溶液和纯水体系中的Suzuki 反应. 结果表明, 水/乙醇混合溶液中 Suzuki 反应速率高于纯水溶液, 其原因可能是反应底物在纯水中溶解性较差所致. 进一步研究发现, 纯水体系中, TBAB 的加入极大地提高了 Suzuki 反应的速率, 并有效地抑制了苯硼酸脱硼副反应的发生.Li 等将一种胍 24 (Scheme 19)/Pd配合物用于室温下的水相Suzuki 反应. 在3 mL 乙醇和水的混合溶液中, Pd 催化剂用量为1 ～2 mol%, 芳基卤代物∶苯硼酸∶K 2CO3 ＝1 ∶1.2∶3( 物质的量比), 室温条件下, 对芳基碘代物、溴代物均表现出较好的催化活性. TBAB的加入还可使芳基氯代物的偶联反应进行.Kostas 等成功将一种水溶性卟啉/Pd 配合物25 Scheme 20)用于纯水相 Suzuki 反应. 催化剂用量为 0.1 mol%, 芳基溴代物∶芳基硼酸∶K 2CO3 ＝1 ∶1.5∶2( 物质的量比), 加热至 100 ℃反应 1 ～4 h, 取得较好的产品收率. 催化剂虽能重复使用但经第二次循环后催化活性明显降低, 产物收率从100%降至76%.Conelly-Espinosa等将一种水溶性N,O-多齿Pd催化剂26 (Scheme 21) 成功用于纯水相 Suzuki 反应. 它可有效催化芳基溴代物的 Suzuki 反应, 反应结束后, 可通过二氯甲烷萃取分出产物, 含有催化剂的水相可高效地循环使用４次.Gülcemal 等将两种水溶性 N,N 或N,O 双齿Pd配合物27 和28 (Scheme 22) 用于纯水相 Suzuki 反应. 此催化体系对芳基溴代物取代基的电子效应比较敏感, 对含吸电子基团的芳基溴代物表现出较高反应活性. 例如对溴苯乙酮与苯硼酸 Suzuki 反应的 TON高达100000而含供电子基团芳基溴代物的偶联反应只有在 TBAB存在下才能顺利进行.Fleckenstein等合成了一系列磺化的 N-杂环卡宾型配体29 和30 (Scheme 23). 研究表明, 此催化体系对含有吸电子或供电子取代基的芳基氯代物均表现出较高的催化活性. 它还对N-杂环芳基氯代物显示较高的催化活性, 例如: 2- 氯吡啶和 2- 氯喹啉可与 1- 萘基硼酸顺利发生Suzuki 反应.Roy 等合成一种磺化的 N-杂环卡宾/Pd 配合物31 (Scheme 24). 它在水/ 正丁醇两相中, 可使芳基氯代物Suzuki 反应顺利进行. 此催化体系还对N-杂芳环氯代物具有较好的催化活性.Godoy 等合成一系列磺化的 N-杂环卡宾/Pd 配合物32 ～35 (Scheme 25). 催化剂对在纯水体系或异丙醇/水体系中的芳基溴代物显示出较好的催化活性. 同时发现, 以催化剂 32的催化活性最高, 在TBAB 存在下还可活化芳基氯代物.Tu等研发了一种水溶性二苯并咪唑基吡啶/Pd 配合物36 (Scheme 26). 在极低的催化剂用量(0.005 mol%)下, 即可在纯水体系中实现水溶性芳基溴代物的 Suzuki反应, 然而, 对于油溶性芳基溴代物则需要有机共溶剂甲醇的存在下, 反应才能顺利进行.Bai 等合成一种水溶性Pd(II)/[SNS]配合物37 Scheme 27), 并用于水相 Suzuki 反应. 在 5 mL 水溶液中, 催化剂用量为 2 mol%, 芳基溴代物∶苯硼酸∶Na2CO3＝0.5∶0.6∶1( 物质的量比), 75 ℃条件下反应 6 h, 4-溴苯乙酮和苯硼酸的收率为100%. 但此催化体系仅对水溶性芳基溴代物表现出较好反应活性.Li 等研究了2- 芳基萘并噁唑环钯配合物 38 (Scheme 28)催化的纯水相 Suzuki 反应发现, 在催化剂用量为0.1 mol% 时, 对含有吸电子、供电子和位阻基团的芳基溴代物均表现出较好的催化活性. 当催化剂负载量提高到1 mol%时, 含吸电子基团的对氯硝基苯也可顺利进行偶联反应, 产物收率为65%.Zhou 等也合成了一类环钯配合物 39 和40 (Scheme 29), 并成功用于纯水相中芳基溴代物的 Suzuki反应. 在催化剂用量为10－5mol% 条件下, 对溴苯甲醚与苯硼酸的 TON高达9.3×10＾6, 催化剂可高效地循环使用5 次.Zhang 等将超声波技术用到纯水相中含杂环二茂铁亚胺异环环钯化合物41 和42 (Scheme 30) 催化的Suzuki 反应. 在催化剂41 用量为0.5～1 mol%, 碱为K 3PO4, TBAB 存在下, 反应温度90 ℃下反应0.5～3 h可高效地催化芳基碘代物和溴代物. 当催化剂换为42时, 芳基氯代物的 Suzuki 反应也可顺利进行. 超声波和常规搅拌方法的对比实验表明, 超声波方法可明显加速Suzuki反应速率.二、非水溶性配体/钯催化的水相Suzuki反应1非离子双亲化合物促进的Suzuki反应Lipshutz 等将一系列非离子双亲化合物作为促进剂用于钯配合物催化的水相 Suzuki 反应. 在对Scheme 31 所列多种非离子双亲化合物的促进效果进行考察后发现, 双亲化合物的加入可有效提高Suzuki 反应速率, 其中以PTS 的效果最为显著. 在水溶液(2 wt% PTS) 中, 催化剂43 (Scheme 32) 用量为 2 mol%, 室温条件下芳基溴代物即可顺利进行 Suzuki 反应. 此催化体系对位阻较大的2,4,6-三异丙基溴苯也具有较高催化活性, 反应 24 h, 收率可达76%. 催化剂 44 (Scheme 32) 则对芳基氯代物显示出较高的催化活性, 2,4- 二甲基氯苯和4- 甲氧基苯硼酸在室温下反应11 h, 收率可达99%.Lipshutz 等还将PTS/H2O 体系应用到杂环芳基溴代物的Suzuki 偶联反应. 在水溶液(2 wt% PTS)中, 催化剂43 (Scheme 32) 用量为 2 mol%, 室温或 40 ℃条件下, 芳基或杂环芳基溴代物和芳基或杂环芳基硼酸可顺利进行Suzuki 反应. 作者还将催化剂 45 (Scheme 33) 用于芳基氯代物的 Suzuki 反应中, 并考察了 PTS, TPGS 和Triton X-100 对Suzuki 反应的影响, 结果发现 PTS (2 wt%)的促进作用也是最明显.对PTS/H2O 体系用于丙烯基醚和芳基硼酸 Suzuki反应(Eq. 5)中的研究结果表明在水溶液(2 wt% PTS)中, 催化剂 46 (Scheme 34) 用量为 2 mol%, 室温条件下, 多种取代基的烯丙基醚和芳基硼酸均可顺利进行Suzuki 反应, 收率为71% ～99%.2. 微波促进的水相Suzuki反应1986 年, Gedye和Giguere等同时发现通过微热加速有机合成反应的现象. 1995 年, Strauss 报道了在密闭反应容器中, 通过微波加热水溶液产生了过热水反应体系. 随着微波技术的发展, 将微波辐射应用于水相有机反应引起了化学家的高度关注.近年, Leadbeater 等首次将微波促进的方法用于过渡金属催化的C—C 偶联反应. 相对于传统加热方式, 微波促进的方法可使长达几小时甚至几十小时的偶联反应缩短至几十分钟乃至几分钟, 且催化剂用量可明显降低到10－6级.2.1 水/ 有机混合溶液反应体系Miao等将催化剂 47 (Scheme 35) 用于芳基氯代物和苯硼酸的 Suzuki 偶联反应. 在V(DMF) ∶V( 水)＝5∶1的混合溶液中, 催化剂47 用量为3 mol%, 芳基氯代物∶苯硼酸∶Cs2CO3 ＝1 ∶1.5∶4( 物质的量比) 时, 在TBAI 存在下, 微波加热至 150 ℃保持 15 min, 反应收率可达99%.Bedford 等制备了一种可有效活化芳基氯代物的催化剂Pd(OAc)2/PCy3. 在二噁烷/ 水( V ∶V ＝6 ∶1) 的混合溶液中, 通过微波加热至 180 ℃, 可使芳基氯代物的Suzuki 反应顺利进行. Zhang等考察了微波加热下用苯基全氟正辛基磺酸盐代替卤代芳烃与苯硼酸的Suzuki 反应(Eq. 6). 在V( 甲苯) ∶V( 丙酮) ∶V( 水) ＝4 ∶4 ∶1 的混合溶液中, 以10 mol% Pd(dppf)Cl2 为催化剂, 微波加热至 130 ℃反应10 min, 产物收率高达 95%. 这种方法的特点在于过量的苯基全氟正辛基磺酸盐容易通过萃取法从反应混合物中分离出来. 微波促进的水相 Suzuki 还广泛应用于药物、天然产物和聚合物的合成研究.Gong 和He将微波促进的水相Suzuki 反应用于 4- 芳基苯丙氨酸化合物的合成(Eq. 7). 在水/ 乙腈( V ∶V ＝1 ∶1) 的混合溶液中, 以PdCl2(PPh3)2 为催化剂, 碱为 Na2CO3, 微波加热至150℃反应 5 ～10 min. 结果表明, 碘代、溴代及氯代芳环化合物均可与 4- 丙氨酰基苯硼酸顺利进行 Suzuki 偶联反应.Han 等以Pd(PPh3)4 为催化剂, 在体积比为 1 ∶1的水/丙酮中, 微波加热至100 ℃, 反应15 min, 可使Eq. 8的溴化荧光素与罗丹明衍生物的 Suzuki 反应获得57% 的收率.Appukkuttan等以Pd(PPh3)4(5 mol%) 为催化剂以水与DMF混合溶液( V∶V＝1∶1) 为溶剂, 考察了微波作用下的2- 溴-4,5- 二甲氧基苯乙胺甲酸酯与苯硼酸的Suzuki 偶联反应(Eq. 9). 结果表明, 相对于传统加热方式, 微波加热方式有明显加速作用. NaHCO3是最适宜的碱, 适宜反应温度为 140 , ℃反应时间为 10 min带有强给电子性、空间位阻较大的芳基溴代物与含有吸电子基团和位阻基团的硼酸均可在微波加热条件下顺利进行Suzuki 反应. 值得指出的是,希望对大家有所帮助，多谢您的浏览！微波加热还可有效避免传统加热条件下苯硼酸自偶联发生.Nehls 等分别以传统加热和微波加热两种方式考察了在水/ 四氢呋喃(THF) 混合溶液中制备一种含聚酮单元的半导体聚合物(Eq.10) 的工艺条件. 在V(THF) ∶V( 水) ＝4 ∶1 的混合溶液中, 以PdCl2(PPh3)2 (4 mol%)为催化剂, 碱为 Na2CO3, 在微波功率分别为 70, 100 和150 W 条件下反应12 min, 相应地得到了分子量为3700, 4200 和12600 的聚合物. 而在传统油浴加热条件下, 要得到相近分子量的聚丙酮需要将反应体系加热到回流状态并保持1 ～3 d.（注：可编辑下载，若有不当之处，请指正，谢谢!）授课：XXX。

经典合成反应标准操作

经典化学合成反应标准操作药明康德新药开发有限公司化学合成部编写、八刖有机合成研究人员在做化学反应经常碰到常规的反应手边没有现成的标准操作步骤而要去查文献，在试同一类反应时，为了寻找各种反应条件方法也得去查资料。

为了提高大家的工作效率，因此化学合成部需要一份〈经典合成反应标准操作》。

另外本版是初版，在今后的工作中我们将根据需要修订这份材料。

药明康德新药开发有限公司化学合成部2005-6-281•胺的合成a）还原胺化b）直接烷基化c）腈的还原d）酰胺的还原e）硝基的还原f）叠氮的还原g） Hoffman 降解h）羧酸通过Cris重排2. 羧酸衍生物的合成a）酰胺化的反应b）酯化反应c）腈转化为酯和酰胺d）钯催化的插羰反应e）酯交换为酰氨3. 羧酸的合成a）醇氧化b）酯水解c）酰胺的水解d）腈的水解e）有机金属试剂的羰基化反应f）芳香甲基的氧化4. 醛酮的合成a） Weinreb酰胺合成醛酮b）醇氧化c）酯的直接还原d）有机金属试剂对腈加成合成酮5•脂肪卤代物的合成a）醇转化为脂肪溴代物通过PBr3转化通过PPh3 与CBr4转化HBr直接交换通过相应的氯代物或磺酸酯与LiBr交换、b）醇转化为脂肪氯代物通过S0CI2转化通过PPh3与CCl4转化HCl直接交换c）醇转化为脂肪碘代物通过PPh3与12转化通过相应的氯代物或磺酸酯与Nal交换6. 芳香卤代物的合成a）San dermyyer 重氮化卤代b）直接卤代c）杂环的酚羟基或醚的卤代7. 醇的合成a）羧酸或酯的还原b）醛酮的还原c）卤代烃的水解d）吡啶的氧化转位8. 酚的合成a）San dermayer 重氮化反应b）醚的水解c）Bayer-vigerlar 氧化d）硼酸的氧化9. 腈的合成a）磺酸酯或卤代烃的取代b）酰胺的脱水c）芳卤代烃的氰基取代10. 硝化反应11. 醚的合成a）芳香醚的合成酚与烷基卤代烃的直接烷基化Mitsu nobu 芳香醚化Buckwald 芳香醚化b）脂肪醚的合成醇的醚化12•脲的合成a）胺与异腈酸酯的反应b）用三光气合成脲c）羰基二咪唑（CDI）合成脲d）对硝基苯酚碳酰胺合成脲13. 烯烃的合成a） Wittig 反应b）羟基的消除c）Wittig-Horner 反应合成,-不饱和酯14. 磺酸及磺酰氯的合成a）氯磺化反应合成磺酰氯b）从硫醇合成磺酰氯c）磺化反应15. 氨基酸的合成a） Streck反应合成b）手性氨基酸的合成16. 偶联反应a） Suzuki Coupli ngb） Buckwald 芳胺化,芳酰胺化、c）Heck反应17. Mitsunobu 反应a）醇的反转b）胺的取代18. 脱羟基反应19. 酮还原为亚甲基20. 氨的保护及脱保护策略a）用碳酰胺作保护基b）苄基保护21. 醇的保护及脱保护策略a）用硅醚进行保护b）其他醚类保护22. 羧基的保护Boc 脱保护1格氏反应还原胺化卤化反应S u z u k i coupling ------------------------------------------------------------------------------------------------ - 2磺化反应n-BuLi -------------------------------------------------------------------------------------------------L i A l H 4 还原 -------------------------------------------------------------------------------------------------- 4P0CI3 的杂环氯代3水解反应-------------------------------------------------------------------------------------------- 5NaH ----------------------------------------------------------------------------------------------------___________NBS ---------------------------------------------------------------------------------------------------———————————氢化反应m-CPBA ----------------------------------------------------------------------------------------------6 EDC ---------------------------------------------------------------------------------------------------6用二光气成脲——7芳卤用n -B u L i i处理后与W e in r e b 酰胺成酮 -------------------------------------------------------------------------------------------------------------------------------------------- 7Boc上保护To a soluti on of A (2.72 g, 13.9 mmol) and tetramethylam monium hydroxide pen tahydrate (5.62 g, 31.0 mmol) in aceto nitrile (270 mL) was added di-tert-butyldicarb on ate (3.79 g; 17.4 mmol) and the resulting solution was allowed to stir 18 h at rt and concentrated. The residue was partitio ned betwee n Et2O/H2O; the phases were separated and the aqueous phase extracted twice more with Et2O. The aqueous phase was brought to pH 4 with solid citric acid and extracted with CHCI3 (3x100 mL). The orga nic extracts were comb in ed, dried (Na2SO4) andconcen trated to afford 2.58 g (63 perce nt) B as a white foam.Boc 脱保护Tert-Butyl 2-(2-methoxyphe no xy)ethylcarbamate (23.8 g, 89 mmol) in dichlorometha ne (10 ml) was cooled to 0 deg C and stirred as a mixture of trifluoroacetic acid: dichloromethane (1:1,40 ml) was added dropwise. The mixture was allowed to warm to rt, stirred for 2 hours and concen trated in vacuo. The residue was take n back up in dichlorometha ne (100 ml) and thesolutio n was washed with saturated aqueous sodium hydroge n carb on ate (3*20 ml) and aqueous sodium hydroxide (10percent, 3*20 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphe no xy)ethylam ine (13 g, 88perce nt yield) as a light yellow solid.Return格氏反应A stirred mixture of magn esium tur nings (23.6 g, 0.98 mol) and Et2O (200 mL) un der n itroge n is treated with a crystal of iodi ne and about 5perce nt of a soluti on of bromoetha ne (56.3 ml, 0.75 mol) in Et2O (375 mL). When the react ion starts, the rema in der of the bromoetha ne solutio n is added, dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring is continued for 1 hour. T o this solution ofethylmagnesium bromide was slowly added a solution of 4-cya nopyridi ne (39 g, 0.375 mol) in Et2O (750 ml). The react ion mixture was warmed at reflux for 12 hours, treated with con ce ntrated H2SO4 (125 ml)/H2O (125 ml), and then washed three times with Et2O (250 ml). The aqueous portio n was made basic (PH 9) with 15perce nt NaOHReturnOsoluti on and extracted five times with 250 ml portions of Et20. The comb ined Et20 extracts were dried (MgSO4), and the solve nt was removed un der reduced pressure to afford a brow n oil (48.4 g, 95perce nt).卤化反应To a stirred solution of 8-methyl-1-nitro-naphthalene (10.6g, 56.32 mmol) and iron (III) chloride (0.45 g, 2.77 mmo) in CCI4 (150 ml) heated to 60 C was added dropwise (3.0 ml, 58.23 mmol) of bromine. After one hour, the react ion mixture was poured into saturated NaHCO3 solutio n, and the layers were separated. The aqueous layer was re-extracted with CH2CI2. The comb ined orga nic layers were dried (MgSO4) and the solve nt was removed un der reduced pressure. The crude residue was recrystallized from etha nol and the mother liquors were concen trated and then flash chromatographed on silica, eludi ng hexa nes:ethyl acetate (12: 1).ReturnReturn还原胺化 HO H 2NA solution of 2-ami no-4-ethylphe nol (1.00 g. 7.28 mmol), 2-naphthaldehyde (1.13 g, 7.28 mmol), and p-tolue nesulfo nic acid (0.05 g) in metha no I (50 ML) was stirred at room temp for 24 h. To the resultant solution, sodium borohydride (0.82 g, 22 mmol) was added in small portions. After additi on was completed, the mixture was stirred at room temperature for 30 min and concen trated un der vacuum. The residue was the n subjected to colu mn chromatography on silica gel eluted with 10percent ethyl acetate in hexane and followed by recrystallization (aqueous metha nol) yielded 450 mg (22perce nt) of an alytically pure product.Retur n+V HSuzuki coupli ngTo a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mnmol)and 3-bromobe nzene (0.87 ml, 8.3 mmol) in THF (28 ml) were added palladium catalystPd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in9 ml of water).The system was degassed and the n charged with n itroge n for three times. Themixture was stirred un der n itroge n at 70 ° C oTlbiatie^i6rheoiliuti on was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethylacetate soluti on was washed by brine, dried over Na2SO4 and concen trated. The residue waspurified on a silica gel colu mn eludi ng with hexa nes: EtOAc 9:1 to give 1.38 g (78%yield) of4-phenyl-1H-indole as a colorless liquid.Return磺化反应Chlorosulfo nic acid (4.66g, 40 mmol) is added dropwise to a cold (0 2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (2.9g, 8 mmol) in chloroform (800 ml).C for 30 minutes. ° The cold bath is then removed and the solution is stirred at room temperature for 1 hour thencautiously poured into ice water. The orga nic layer is separated, dried over magn esium sulfate and concen trated to afford the titlecompo und. The crude product is purified by colu mn chromatography eluted with 10% acetic ether in petroleum ether (2.36 g, 81% yield).酯化反应A mixture of 4-hydroxymethy In aphthoic acid (10 g, 50 mmol), metha no I (300 ml), and concen trate H2SO4 (2 ml) was refluxed overni ght. The in solubles were filtered off and the filtrate was concen trated. The residue was take n up in ethyl acetate and washed with aqueous NaHCO3 (2*), brine, dried over MgSO4, and concen trated to give a yellow oil. Silica gel colu mn chromatography using ethyl acetate/hexa ne (1/3) gave the desired product as a yellow oil (3.3 g,35%yield).Retur nC) solutio n ofThe result ing soluti on is stirred at 0HOHO水解反应sodium hydroxide (35ml) in tetrahydrofura n (130ml) was stirred un der reflux for 18 hours. The mixture was n eutralised using 2N hydrochloric acid, and extracted with dichlorometha ne (3x).The comb ined orga nic soluti ons were dried (MgSO4), and evaporated un der reduced pressure. The crude product was purified by column chromatography on silica gelusing an gradient of dichloromethane: methanol (100:0 to 97:3) to afford the title compound as a solid (3.11g,47.8%yield).硝化反应NO2To a cold (0 °C) suspension of 1-methylnaphthalene (5 g, 35.2 mmol) in HNO3 was added H2SO4 (5 ml) dropwise. After stirri ng the react ion for one hour, the soluti on was diluted with ethyl acetate and washed with water (3*), aqueous saturated NaHCO3 (2*) and brine, dried over MgSO4, and concen trated. The product was purified by silica gel colu mn chromatography using ReturnA solution of 1-Methyl-naphthalene-2-carboxylicacid methyl ester (7.20g, 35mmol) and 2NelutionRetur nOHethyl acetate: hexa ne (5: 95) and recrystallized from metha nol to give yellow n eedles (0.22g, 33% yield).n-BuLiTo a dry three-n ecked roun d-bottomed flask with an additi on funnel and at -78 inertatmosphere was charged with an hydrous THF (500 ml). A soluti on of n-butyllithium (2.5 Min hexane, 88 ml, 220 mmol) was added dropwise followed by addition of a solution of aceton itrile (10.43 ml, 200 mmol) in an hydrous THF (100 ml). The in ternal temperature wasmaintained below -70 °C duri ng the en tire additi on process. After 2 hr at -78 °C a soluti on of Trifluoro-acetic acid ethyl ester (14.2 g, 100 mmol) in an hydrous THF (30 ml) was added dropwise and the mixture was stirred for 1.5 hr. T o the mixture was added acetic an hydride to que nch the react ion. The reacti on mixture was allowed to warm up to rt. A precipitate was filtered and the filtrate was concentrated to give a brown oil, which was used in the next step withoutpurificatio n.ReturnLiAlH4还原A solution of 2,3-naphthale nedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 ml, warmed toReturn°C under O50 ° to maintain solution) is added dropwise over 15 minutes to a 1.15 M lithium aluminum hydride solution in THF (45 ml, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully with THF-water, then 2N hydrochloric acid (40 ml) is added, and the resulting mixture is extracted 3 times with ether. The comb ined ether extracts are washed with water (2 times), with saturated sodium bicarb on ate soluti on (1 time), with water, and are dried (sodium sulfate), filtered, and concentrated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g, 67.3%yield) as a light tan crystalline material.Retur n POCI3的杂环氯代HO ClTo a suspension of 2,4-dihydroxy-5,6-dimethylpyrimidine (6.2 g, 0.044 mol) in POCl3 (25 ml) wasslowly added N,N-dimethyla nili ne (6.18 ml, 0.049 mol). The mixture was then refluxed at 125 Cfor 3 hours. After this time, the starti ng material completely dissolved in dicat ing that the reactio n was completed. The react ion mixture was cooled and the n poured slowly onto ice to que nchthe POCl3 (cauti on[ exothermic]). A precipitate formed, which was filtered and washed withice-cold water. The precipitate was dried un der high vacuum overni ght to yield2,4-dichloro-5,6-dimethyl-pyrimidine (7.2 g, 0.041 mol, 92%yield) as a yellow solid.Retur nNaHSodium hydride (50% in min eral oil, 5.5 g, 0.11 mol) was added porti on wise at 0 nitrogen atmosphere to a solution of 2-aminobenzenethiol (12 ml, 0.1 mol) in DMF (120 ml).After 0.5 h, ben zyl chloride (11.5 ml, 0.1 mol) in DMF (80 ml) was added in 0.5 h. The solutionwas stirred for 3 h while the temperature was allowed to rise to rt, then it was poured into ice/water (1000 g). The precipitate was filtered, dissolved in ethyl acetate and washed with brine. Theorga nic layer was dried over Na2SO4 and evaporated. The solid obta ined was ground in pentane (19.3 g, 90% yield).NBSA mixture of 2,4-Dichloro-6-ethyl-5-fluoro-pyrimid ine (27.46 gand n-bromosucci nimide (27.02 g , 0.152mol) in CH2Cl2 (170 ml) wasrefluxed un der a nitroge natmosphere for 36 h. Then washed by water, the aqueous was extracted by CH2Cl2. The comb ined orga nic layer was washed by saturated Na2S2O3 and brine, dried over Na2SO4, and evaporated to give a white solid which was purified by colu mn chromatography eluted with 50% acetic ether in petroleum ether (34 g, 88.6%yield).°C under aRetur nNBS,0.14mol), AIBN (1.32 g)H 2NClClClm-CPBAA solution of 85% m-chloroperoxybe nzoic acid (19 g, 94 mmol) in CH2Cl2 (350 ml)was added at—-0 °C to a solution of 2-Benzylsulfanyl-phenylamine (19 g, 88 mmol) in CH2Cl2 (400 ml). Themixture was allowed to warm to rt in 3 h, then it was washed with a 5% Na2S2O3 soluti on, 10%NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and evaporated. Thesolid was ground in pentane (19 g, 95% yield).Return 氢化反应A mixture of ethyl 3-(N-be nzylam ino )-3-methylbutyrate hydrochloride (25g, 0.1 mol) andlOperce nt Pd-C (2g) in 250 ml of dried alcohol was hydroge nated un der 55 psi H2 for four days.The react ion medium was the n filtered and evaporated un der reduced pressure to provide anamber oil which gradually crystallized upon sta nding (18 g, 100% yield).Retur nHClNH 2ReturnEDCOTo a 0 ° C mixture of BoL-tyrosine (2.04 g, 7.26 mmol) and amylamine (0.63 gl, 7.26 mmol) inmethyle ne chloride (30 ml) is added 1-(3-dimethylami nopropyl)-3-ethylcarbodiimide (EDC) (1.53 resulting solution is diluted with methylene chloride (30 ml) and washed successively with 0.5 M HCl (40 ml), water (20 ml) and sat aq sodium bicarb on ate (25 ml). The orga nic phase is dried over magn esium sulfate and concen trated to a foam (1.84 g, 72.4%yield), sufficie ntly pure to carry into the n ext step. An an alytical sample is obta ined by HPLC.g, 9.9 mmol ). The white mixture is stirred at 0 C for 5 min and at room temp for 23 hrs. TheRetur n三光气成脲To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) in toluene (10 ml)triethylamine (0.13 ml, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. Thereaction mixture was stirred at 70 ° C for 2 hours, the n cooled to room temperature. Then more 2-(tert -butyldimethylsilyloxy)- 4-n itroa nil ine (200 mg, 0.75 mmol) was added. The result ingmixture was allowed to stir at 70 ° C for 48 hours the n cooled to room temperature. The react ion mixture was partiti oned betwee n water and ethyl acetate. The comb ined orga nic phase waswashed with brine, dried over MgSO4 and filtered. Removal of solve nt at reduced pressure andchromatography of the result ing oil on silica gel (hexa ne: ethyl acetate, 10:1) gave 1,3-Bis-(2-hydroxy-4-nitro-phenyl)-urea (130 mg, 31%yield). Retur n 芳卤用n-BuLi 处理后与Weinreb 酰胺成酮To a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at argon wasadded n-butyllithium (54.0 ml, 2.5M in hexa ne, 0.135 mole), followed after 5 min bydropwise a solution of 2-fluoro-4-methylpyrid ine (10 g, 0.090 mole) in THF (20 ml). After stirri ng for 15 min at -78 ° C, a solution of Nmethoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 ml) was added dropwise. After stirri ng for more 5 mi n, the react ion wasC and que nched by pouri ng into w^teo ml) and ethyl acetate (400 ml).The layers were separated, and the aqueous layer washed with ethyl acetate (200 ml). The ethyl acetate extracts were comb in ed, dried over an hydrous sodium sulfate, filtered, and concen trated to an oil whichCl O O Cl心丁 3NO 2—78 ° C underallowed to warm to 0was chromatographed on silica gel with 20perce nt ethyl acetate in hexa ne to give 21.6 g of 2-(2-Fluoro-pyridi n-4-yl)-1-(3-trifluoromethyl-phe nyl)-etha none (84.8%yield).Return。

suzuki反应

Pd(OAc)2 THF K2CO3 rt2h
C8H7O OH
b b + I
O Br
NaH DMF 40oC 4h
C8H7O O O I
联苯类液晶单元的合成路线
董万荣,具有潜在液晶性能的光学活性双螺旋衍生物的设计与合成[D],湖南大学,有机化学,2009.
有机偏振发光材料
Br N R Br OH CnH2n+1Br K2CO3/acetone R Pd(PPh3)4/K2CO3 toluene, ethanol H2n+1CnO N OCnH2n+1 Br OH CnH2n+1Br NaH DMF Br N
铃木章凭借研发“有机合成中的钯催化的交叉偶联”与美国科学家理查德赫克、日本科学家根岸英一共同获得2010年诺贝尔化学奖。
反应方程式
•
R1,R2=芳基，乙烯基，炔基
反应物
• Suzuki反应对官能团的耐受性非常好，反应物可以带着-CHO、-COCH3、-COOC2H5、-OCH3、-CN、-NO2、 -F等官能团进行反应而不受影响。反应有选择性，不同卤素、以及不同位置的相同卤素进行反应的活性可能有差别，三氟甲磺酸酯、重氮盐、碘鎓盐或芳基锍盐和芳基硼酸也可以进行反应。 • 另一个底物一般是芳基硼酸，由芳基锂或格氏试剂与烷基硼酸酯反应制备。
反应背景
• 1979年，铃木研究组在两篇文章中报导了有机硼化合物在碱的作用下，能与乙烯基或芳基卤化物在钯的催化作用下发生偶联反应，碱活化了有机硼试剂，形成的中间体促进了R从硼迁移到钯，这个反应后来被扩展到烷基的反应。另外一个重大的发现，就是芳基硼酸也能发生这个反应，在后来的例子中发现活性更高或更弱的碱也能参与反应。 • 稳定而亲核性较弱的硼试剂能使这个反应更实用，它无毒，在较温和的反应条件下进行，使它在制药工业中广为流行。

suzuki偶联反应的详细反应机理

suzuki偶联反应的详细反应机理Suzuki偶联反应是一种重要的有机合成方法，可以将芳香化合物上的芳香环与有机卤化物进行偶联反应，形成新的碳-碳键。

该反应由日本化学家Suzuki Kiyoshi于1979年首次发表，因其高效、高选择性和宽广的适用范围而受到广泛关注和应用。

Suzuki偶联反应的机理可以分为四个关键步骤：氧化加成、络合物生成、还原消除和脱碘。

下面将详细介绍这四个步骤。

首先是氧化加成步骤。

在反应开始时，有机卤化物（如溴代芳烃）与芳香硼酸酯在碱性条件下加热反应，生成芳香硼酸盐。

这一步骤是由于有机卤化物的亲电性，它与碱性条件下的硼酸酯发生亲核取代反应，生成新的碳-硼键。

接下来是络合物生成步骤。

芳香硼酸盐与钯（Pd）络合物催化剂发生络合作用，形成稳定的芳香硼酸盐-钯络合物。

这一步骤是关键的中间步骤，它使得反应物质更容易发生偶联反应，并提高了反应的效率和选择性。

然后是还原消除步骤。

在芳香硼酸盐-钯络合物的存在下，加入碱性还原剂（如碳酸钠），将芳香硼酸盐中的硼原子还原为亲核性更强的芳香基，同时脱去反应物质中的卤素基团。

这一步骤是通过亲核取代反应和消除反应的结合，实现了新的碳-碳键的形成。

最后是脱碘步骤。

在经过还原消除步骤后，反应物中仍然存在着一定量的碘离子。

为了进一步净化产物，需要加入脱碘试剂（如亚砜），将碘离子与试剂发生反应，生成易于分离的无机盐。

总体而言，Suzuki偶联反应的机理是一个复杂的多步骤反应过程。

通过氧化加成、络合物生成、还原消除和脱碘等关键步骤，可以将芳香化合物上的芳香环与有机卤化物进行偶联反应，形成新的碳-碳键。

这一反应机理的详细了解和理解，有助于我们更好地设计和优化相关有机合成方法，为有机合成化学提供更多的可能性和应用。

关于Suzuki反应

关于Suzuki反应关于Suzuki反应1 Suzuki的详细介绍自从1979年Suzuki等报道了通过钯催化的有机硼化学物和卤代烃可以在很温和的条件下发生偶联反应制备不对称联芳烃以后，为芳-芳键的形成展开了一个新的领域。

目前，Suzuki-Miyaura交叉偶联反应已逐渐成为现代有机合成中关于碳-碳键的生成的最为有效的方法之一。

最近十年来，Suzuki-Miyaura交叉偶联反应通常是在很温和的条件下，不受水以及很多官能团的影响，这种反应被大量用在实验室制备药物以及精细化工中合成大量的有用的有机中间体。

尽管还有别的方法如Heck偶联反应，Negishi偶联反应，Stille偶联反应，Himama 偶联反应，Sonogashira偶联反应和Kumuda偶联反应等也可以达到同样的目的。

但是Suzuki-Miyaura偶联反应被证明是目前制备联芳基及其衍生物最为广泛利用的方法，与其他钯催化的偶联反应相比，Suzuki-Miyaura偶联反应主要有以下几个优点：首先，反应条件相对较温和而且所用的各种硼酸及其衍生物相对于其他偶联反应中所用的有机金属试剂对环境是很稳定的，容易保存，也容易处理。

其次，反应的后处理很容易，且含硼副产物相对于别的有机溶剂容易除去，这对于工业生产来说是很有优势的。

再次，反应中所用到的硼试剂相对于很多的官能团（例如羰基，羟基，氨基等）都是很稳定的，这是由于硼原子的电负性（2.0）接近碳原子的电负性（2.5），而大大高于锂，镁以及大多数其他的过渡金属原子（电负性值介于0.85-1.75之间）。

最后，由于其使用的是低毒性的硼试剂并产生无毒的硼副产物，为用绿色化学合成碳-碳键提供了一条有效途径。

Suzuki-Miyaura交叉偶联的反应机理通常是被认为是一个普通的催化循环过程这个过程主要包括三个步骤，它们分别是：（1）氧化加成（oxidative addition）；（2）转移金属化（transmetalation）；（3）还原消除（reductive elimination）。

药明康德Level 2题目-烃化反应

是非题:1.采用卤代烷对醇进行烷基化反应，氟代烷活性最高，碘代烷活性最低。

（）2.碱性条件下，烷氧负离子进攻环氧化合物开环，主要受电性控制，进攻发生在取代较多的碳原子上。

（）3.由于酚负离子亲核性比烷氧基负离子弱，以卤代烷为烷基化剂，酚的烷基化反应较醇难以进行，需要采用更强的碱。

（）4.邻羟基苯甲酸与对羟基苯甲酸相比，由于邻羟基苯甲酸含有分子内氢键，酚羟基酸性更强，烃化反应更容易进行。

（）5.硫酸二甲酯是一种常用的甲基化试剂，由于硫酸二甲酯含有两个甲基，可以甲基化两个当量的醇。

（）6.硫酸二甲酯活性较碘甲烷弱，一般只能用于甲基化醇，不能用于甲基化酚。

（）7.羧酸比酚更容易被重氮甲烷甲基化。

（）8.DCC不仅可以用于酸和醇缩合，也可用于酚和醇缩合生成醚。

（）9.Mitsunobu反应用于手性醇对酚的烷基化反应中，手性醇的构型会发生反转。

（）10.醇在碱性条件下与芳基卤代物发生亲核取代反应，碘代芳烃活性最低，氟代芳烃活性最高。

（）11.Cu催化的芳基卤化物与芳香胺的偶联反应中，碘代芳烃活性最低，氟代芳烃活性最高。

（）12.Chan-Lam偶联是铜催化下的硼酸或硼酯与胺，酚或醇等的反应，和Suzuki反应类似，Chan-Lam偶联对氧气比较敏感，需要在惰性气体保护下进行，但对水不敏感，加水一般可以促进反应。

（）13.Friedel-Crafts烷基化反应中，伯卤代烷由于位阻最小，反应活性也最高。

（）14.Friedel-Crafts烷基化反应中，氟代烷反应活性最高，碘代烷活性最低。

（）15.三氯化铝是Friedel-Crafts反应中最常用的催化剂，但一般不适用于催化富电子杂环如呋喃或吡咯的烷基化。

( )16.叔卤代烷由于在碱性条件下易消除，一般不适用于活泼亚甲基化合物的烷基化。

( )17.酮的α位碳在碱性条件下拔氢，在动力学控制条件下易于生成取代基少的烯醇负离子。

( )18.由于醛在碱性条件下易发生羟醛缩合，对醛的α位烷基化可以采用烯胺烷基化的间接方法。

药明康德培训测试题(PartII)

化学合成部专业知识第二次培训试题姓名：项目组：得分：第一部分：氨基的保护与脱保护（40 分）1.1 以下各种胺保护基在使用时各有什么优缺点（20 分）？1.2 写出用TFA 脱Boc 时的反应式，阐述若分子内有对酸敏感的官能团或容易捕捉碳正离子的官能团时，我们选用什么反应条件。

（6 分）：ON HO RHCldioxane1.3 写出以下选择性上保护和脱保护的条件。

（3 分）：1.4 对于胺上苄基脱保护时，为什么常常这个反应需要加酸或者Boc 酸酐，醋酸酐等（3 分）1.5 对于胺上苄基无法通过加氢脱除时，还有那些方法脱保护，最常用的为那一种（2 分）1.6 写出以下选择性脱保护的条件（5 分）第二部分： Pd催化的偶联反应（20分）2.1 写出Suzuki coupling, Heck reaction, Sonogashira coupling 及Stille Coupling的反应通式（12 分）？Suzuki couplingHeck reactionSonogashira couplingStille Coupling2.2 为什么Suzuki, Heck 和Sonogashira 反应在用钯催化剂和膦配体需要无氧操作（2 分）2.3 Suzuki Coupling芳香硼酸及硼酸酯的制备方法（4 分）：2.4为什么Suzuki, Heck 和Sonogashira 反应常常会出现脱卤的副产物（2 分）第三部分：胺的合成（20 分）3.1 以下四种还原合成胺的反应条件（12 分）？3.2 Curtius 重排将酸变为少一个碳的反应机理（3 分）3.3 写出DPPA结构，为什么用DPPA可以将脂肪的伯醇和仲醇直接转变为相应的叠氮（3 分）第四部分：脲与硫脲的合成（10 分）4.1 写出五种以上合成脲的方法（5 分）4.2 写出五种以上合成硫脲的方法（2 分）4.3 请写出利用羰基二咪唑合成脲的反应式，该反应操作应该注意什么（3 分）第五部分：综合-利用所学相关反应设计以下合成路线（10 分）N H N HOClNH2Cl。

经典合成反应标准操作

为了提高大家的工作效率，因此化学合成部需要一份《经典合成反应标准操作》。

另外本版是初版，在今后的工作中我们将根据需要修订这份材料。

药明康德新药开发有限公司化学合成部2005-6-28目录1.胺的合成a)还原胺化b)直接烷基化c)腈的还原d)酰胺的还原e)硝基的还原f)叠氮的还原g)Hoffman降解h)羧酸通过Cris 重排2.羧酸衍生物的合成a)酰胺化的反应b)酯化反应c)腈转化为酯和酰胺d)钯催化的插羰反应e)酯交换为酰氨3.羧酸的合成a)醇氧化b)酯水解c)酰胺的水解d)腈的水解e)有机金属试剂的羰基化反应f)芳香甲基的氧化4.醛酮的合成a)Weinreb 酰胺合成醛酮b)醇氧化c)酯的直接还原d)有机金属试剂对腈加成合成酮5.脂肪卤代物的合成a)醇转化为脂肪溴代物通过PBr3 转化通过PPh3 与CBr4 转化HBr直接交换通过相应的氯代物或磺酸酯与LiBr交换、b)醇转化为脂肪氯代物通过SOCl2转化通过PPh3 与CCl4 转化HCl直接交换c)醇转化为脂肪碘代物通过PPh3 与I2 转化通过相应的氯代物或磺酸酯与NaI交换6.芳香卤代物的合成a)Sandermyyer 重氮化卤代b)直接卤代c)杂环的酚羟基或醚的卤代7.醇的合成a)羧酸或酯的还原b)醛酮的还原c)卤代烃的水解d)吡啶的氧化转位8.酚的合成a)Sandermayer 重氮化反应b)醚的水解c)Bayer-vigerlar 氧化d)硼酸的氧化9.腈的合成a)磺酸酯或卤代烃的取代b)酰胺的脱水c)芳卤代烃的氰基取代10.硝化反应11.醚的合成a)芳香醚的合成酚与烷基卤代烃的直接烷基化Mitsunobu 芳香醚化Buckwald芳香醚化b)脂肪醚的合成醇的醚化12.脲的合成a)胺与异腈酸酯的反应b)用三光气合成脲c)羰基二咪唑（CDI）合成脲d)对硝基苯酚碳酰胺合成脲13.烯烃的合成a)Wittig 反应b)羟基的消除c)Wittig-Horner 反应合成,-不饱和酯14.磺酸及磺酰氯的合成a)氯磺化反应合成磺酰氯b)从硫醇合成磺酰氯c)磺化反应15.氨基酸的合成a)Streck 反应合成b)手性氨基酸的合成16.偶联反应a)Suzuki Couplingb)Buckwald 芳胺化，芳酰胺化、c)Heck 反应17.Mitsunobu 反应a)醇的反转b)胺的取代18.脱羟基反应19.酮还原为亚甲基20.氨的保护及脱保护策略a)用碳酰胺作保护基b)苄基保护21.醇的保护及脱保护策略a)用硅醚进行保护b)其他醚类保护22.羧基的保护Boc脱保护-------------------------------------------------------------------------------------------------------1 格氏反应---------------------------------------------------------------------------------------------------------1还原胺化---------------------------------------------------------------------------------------------------------2卤化反应---------------------------------------------------------------------------------------------------------2S u z u k i coupling------------------------------------------------------------------------------------------------- 2 磺化反应---------------------------------------------------------------------------------------------------------3酯化反应---------------------------------------------------------------------------------------------------------3水解反应---------------------------------------------------------------------------------------------------------3硝化反应---------------------------------------------------------------------------------------------------------4n-BuLi------------------------------------------------------------------------------------------------------------ 4 L i A l H4还原-----------------------------------------------------------------------------------------------------4 P O C l3的杂环氯代----------------------------------------------------------------------------------------------5 NaH--------------------------------------------------------------------------------------------------------------- 5 NBS--------------------------------------------------------------------------------------------------------------- 5 氢化反应---------------------------------------------------------------------------------------------------------6m-CPBA---------------------------------------------------------------------------------------------------------- 6 EDC--------------------------------------------------------------------------------------------------------------- 6用三光气成脲---------------------------------------------------------------------------------------------------7 芳卤用n-BuLi 处理后与Wei nr eb酰胺成酮-----------------------------------------------------------------7Boc 上保护OHH 2NHO OOO OOO OHN HO OHO O A BTo a solution of A (2.72 g, 13.9 mmol) and tetramethylammonium hydroxide pentahydrate (5.62 g, 31.0 mmol) in acetonitrile (270 mL) was added di-tert-butyldicarbonate (3.79 g; 17.4 mmol) and the resulting solution was allowed to stir 18 h at rt and concentrated. The residue was partitioned between Et2O/H2O; the phases were separated and the aqueous phase extracted twice more with Et2O. The aqueous phase was brought to pH 4 with solid citric acid and extracted with CHCl3 (3.x.100 mL). The organic extracts were combined, dried (Na2SO4) and concentrated to afford 2.58 g (63 percent) B as a white foam.ReturnBoc 脱保护OON HOO OOH 2NTert-Butyl 2-(2-methoxyphenoxy)ethylcarbamate (23.8 g, 89 mmol) in dichloromethane (10 ml) was cooled to 0 deg C and stirred as a mixture of trifluoroacetic acid: dichloromethane (1:1, 40 ml) was added dropwise. The mixture was allowed to warm to rt, stirred for 2 hours and concentrated in vacuo. The residue was taken back up in dichloromethane (100 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate (3*20 ml) and aqueous sodium hydroxide (10percent, 3*20 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide 2-(2-methoxyphenoxy)ethylamine (13 g, 88percent yield) as a light yellow solid.Return格氏反应NCNNOA stirred mixture of magnesium turnings (23.6 g, 0.98 mol) and Et2O (200 mL) under nitrogen is treated with a crystal of iodine and about 5percent of a solution of bromoethane (56.3 ml, 0.75 mol) in Et2O (375 mL). When the reaction starts, the remainder of the bromoethane solution is added, dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring is continued for 1 hour. T o this solution of ethylmagnesium bromide was slowly added a solution of 4-cyanopyridine (39 g, 0.375 mol) in Et2O (750 ml). The reaction mixture was warmed at reflux for 12 hours, treated with concentrated H2SO4 (125 ml)/H2O (125 ml), and then washed three times with Et2O (250 ml). The aqueous portion was made basic (PH 9) with 15percent NaOHsolution and extracted five times with 250 ml portions of Et2O. The combined Et2O extracts were dried (MgSO4), and the solvent was removed under reduced pressure to afford a brown oil (48.4 g, 95percent).Return还原胺化OHO H 2N+HON HA solution of 2-amino-4-ethylphenol (1.00 g. 7.28 mmol), 2-naphthaldehyde (1.13 g, 7.28 mmol), and p-toluenesulfonic acid (0.05 g) in methanol (50 ML) was stirred at room temp for 24 h. To the resultant solution, sodium borohydride (0.82 g, 22 mmol) was added in small portions. After addition was completed, the mixture was stirred at room temperature for 30 min and concentrated under vacuum. The residue was then subjected to column chromatography on silica gel eluted with 10percent ethyl acetate in hexane and followed by recrystallization (aqueous methanol) yielded 450 mg (22percent) of analytically pure product.Return卤化反应O 2NO 2NBrTo a stirred solution of 8-methyl-1-nitro-naphthalene (10.6g, 56.32 mmol) and iron (III) chloride (0.45 g, 2.77 mmo) in CCl4 (150 ml) heated to 60°C was added dropwise (3.0 ml, 58.23 mmol) of bromine. After one hour, the reaction mixture was poured into saturated NaHCO3 solution, andthe layers were separated. The aqueous layer was re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. The crude residue was recrystallized from ethanol and the mother liquors were concentrated and then flash chromatographed on silica, eluding hexanes:ethyl acetate (12: 1).ReturnSuzuki couplingBrBOO NH+NH To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (2 g, 8.2 mnmol) and 3-bromobenzene (0.87 ml, 8.3 mmol) in THF (28 ml) were added palladium catalystPd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 ml of water).The system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70 °C oil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluding with hexanes: EtOAc 9:1 to give 1.38 g (78%yield) of4-phenyl-1H-indole as a colorless liquid.Return磺化反应NOFFFNOFFFSOClOChlorosulfonic acid (4.66g, 40 mmol) is added dropwise to a cold (0°C) solution of2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline (2.9g, 8 mmol) in chloroform (800 ml). The resulting solution is stirred at 0°C for 30 minutes. The cold bath is then removed and the solution is stirred at room temperature for 1 hour then cautiously poured into ice water. The organic layer is separated, dried over magnesium sulfate and concentrated to afford the title compound. The crude product is purified by column chromatography eluted with 10% acetic ether in petroleum ether (2.36 g, 81% yield).Return 酯化反应HOHO O HOO OA mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 ml), and concentrate H2SO4 (2 ml) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO3 (2*), brine, dried over MgSO4, and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%yield).Return水解反应OO OHOA solution of 1-Methyl-naphthalene-2-carboxylic acid methyl ester (7.20g, 35mmol) and 2N sodium hydroxide (35ml) in tetrahydrofuran (130ml) was stirred under reflux for 18 hours. The mixture was neutralised using 2N hydrochloric acid, and extracted with dichloromethane (3x). The combined organic solutions were dried (MgSO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gelusing an elution gradient of dichloromethane: methanol (100:0 to 97:3) to afford the title compound as a solid (3.11g, 47.8%yield).Return硝化反应2To a cold (0°C) suspension of 1-methylnaphthalene (5 g, 35.2 mmol) in HNO3 was added H2SO4 (5 ml) dropwise. After stirring the reaction for one hour, the solution was diluted with ethyl acetate and washed with water (3*), aqueous saturated NaHCO3 (2*) and brine, dried over MgSO4, and concentrated. The product was purified by silica gel column chromatography usingethyl acetate: hexane (5: 95) and recrystallized from methanol to give yellow needles (0.22g, 33% yield).Returnn-BuLiEtOCF 3O CF 3O NCTo a dry three-necked round-bottomed flask with an addition funnel and at -78°C under inert atmosphere was charged with anhydrous THF (500 ml). A solution of n-butyllithium (2.5 M in hexane, 88 ml, 220 mmol) was added dropwise followed by addition of a solution of acetonitrile (10.43 ml, 200 mmol) in anhydrous THF (100 ml). The internal temperature was maintained below -70°C during the entire addition process. After 2 hr at -78°C a solution of Trifluoro-acetic acid ethyl ester (14.2 g, 100 mmol) in anhydrous THF (30 ml) was added dropwise and the mixture was stirred for 1.5 hr. T o the mixture was added acetic anhydride to quench the reaction. The reaction mixture was allowed to warm up to rt. A precipitate was filtered and the filtrate was concentrated to give a brown oil, which was used in the next step without purification.ReturnLiAlH4还原HOHO O HOHOA solution of 2,3-naphthalenedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 ml, warmed to50° to maintain solution) is added dropwise over 15 minutes to a 1.15 M lithium aluminum hydride solution in THF (45 ml, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully with THF-water, then 2N hydrochloric acid (40 ml) is added, and the resulting mixture is extracted 3 times with ether. The combined ether extracts are washed with water (2 times), with saturated sodium bicarbonate solution (1 time), with water, and are dried (sodium sulfate), filtered, and concentrated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g, 67.3%yield) as a light tan crystalline material.ReturnPOCl3的杂环氯代NN HO OHNClClTo a suspension of 2,4-dihydroxy-5,6-dimethylpyrimidine (6.2 g, 0.044 mol) in POCl3 (25 ml) was slowly added N,N-dimethylaniline (6.18 ml, 0.049 mol). The mixture was then refluxed at 125 °C for 3 hours. After this time, the starting material completely dissolved indicating that the reaction was completed. The reaction mixture was cooled and then poured slowly onto ice to quench the POCl3 (caution[exothermic]). A precipitate formed, which was filtered and washed with ice-cold water. The precipitate was dried under high vacuum overnight to yield2,4-dichloro-5,6-dimethyl-pyrimidine (7.2 g, 0.041 mol, 92%yield) as a yellow solid.ReturnNaHHSH 2N Cl+SNH 2Sodium hydride (50% in mineral oil, 5.5 g, 0.11 mol) was added portionwise at 0 °C under a nitrogen atmosphere to a solution of 2-aminobenzenethiol (12 ml, 0.1 mol) in DMF (120 ml). After 0.5 h, benzyl chloride (11.5 ml, 0.1 mol) in DMF (80 ml) was added in 0.5 h. The solution was stirred for 3 h while the temperature was allowed to rise to rt, then it was poured into ice/water (1000 g). The precipitate was filtered, dissolved in ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and evaporated. The solid obtained was ground in pentane (19.3 g, 90% yield).ReturnNBSNN FCl ClN N FCl ClBrA mixture of 2,4-Dichloro-6-ethyl-5-fluoro-pyrimidine (27.46 g ， 0.14mol), AIBN (1.32 g) and n-bromosuccinimide (27.02 g ， 0.152mol) in CH2Cl2 (170 ml) was refluxed under a nitrogen atmosphere for 36 h. Then washed by water, the aqueous was extracted by CH2Cl2. The combined organic layer was washed by saturated Na2S2O3 and brine, dried over Na2SO4, and evaporated to give a white solid which was purified by column chromatography eluted with 50% acetic ether in petroleum ether (34 g, 88.6% yield).Return 氢化反应O ONH OONH2Cl ClA mixture of ethyl 3-(N-benzylamino)-3-methylbutyrate hydrochloride (25g, 0.1 mol) and10percent Pd-C (2g) in 250 ml of dried alcohol was hydrogenated under 55 psi H2 for four days. The reaction medium was then filtered and evaporated under reduced pressure to provide an amber oil which gradually crystallized upon standing (18 g, 100% yield).Returnm-CPBAS NH2SNH2OA solution of 85% m-chloroperoxybenzoic acid (19 g, 94 mmol) in CH2Cl2 (350 ml)was added at –5 – 0 °C to a solution of 2-Benzylsulfanyl-phenylamine (19 g, 88 mmol) in CH2Cl2 (400 ml). The mixture was allowed to warm to rt in 3 h, then it was washed with a 5% Na2S2O3 solution, 10% NaHCO3 solution and brine. The organic layer was dried over Na2SO4, and evaporated. The solid was ground in pentane (19 g, 95% yield).ReturnEDCNH 2O+H OTo a 0°C mixture of Boc -L-tyrosine (2.04 g, 7.26 mmol) and amylamine (0.63 gl, 7.26 mmol) in methylene chloride (30 ml) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (1.53 g, 9.9 mmol ). The white mixture is stirred at 0°C for 5 min and at room temp for 23 hrs. The resulting solution is diluted with methylene chloride (30 ml) and washed successively with 0.5 M HCl (40 ml), water (20 ml) and sat aq sodium bicarbonate (25 ml). The organic phase is dried over magnesium sulfate and concentrated to a foam (1.84 g, 72.4%yield), sufficiently pure to carry into the next step. An analytical sample is obtained by HPLC.Return三光气成脲NH 2ONO 2Si O Cl ClO Cl ClO 2NH N H NOHOHNO 2+To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) in toluene (10 ml) triethylamine (0.13 ml, 1.64 mmol) and triphosgene (88.4 mg, 0.3 mmol) were added. The reaction mixture was stirred at 70 °C for 2 hours, then cooled to room temperature. Then more 2-(tert -butyldimethylsilyloxy)-4-nitroaniline (200 mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70 °C for 48 hours then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane: ethyl acetate, 10:1) gave 1,3-Bis-(2-hydroxy-4-nitro-phenyl)-urea (130 mg, 31%yield).Return芳卤用n-BuLi 处理后与Weinreb 酰胺成酮N FF FFN O O+F FF ONFTo a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at –78°C underargon was added n-butyllithium (54.0 ml, 2.5M in hexane, 0.135 mole), followed after 5 min by dropwise a solution of 2-fluoro-4-methylpyridine (10 g, 0.090 mole) in THF (20 ml). After stirring for 15 min at –78°C, a solution of N -methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 ml) was added dropwise. After stirring for more 5 min, the reaction wasallowed to warm to 0°C and quenched by pouring into wate r (400 ml) and ethyl acetate (400 ml). The layers were separated, and the aqueous layer washed with ethyl acetate (200 ml). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20percent ethyl acetate in hexane to give 21.6 g of 2-(2-Fluoro-pyridin-4-yl)-1-(3-trifluoromethyl-phenyl)-ethanone (84.8%yield).Return。

suzuki 交叉偶联反应

Suzuki 交叉偶联反应简介Suzuki 交叉偶联反应是一种重要的有机合成方法，其可用于构建碳-碳键和碳-氮键。

该反应以钯催化剂为基础，通过将有机卤化物与有机硼试剂偶联，实现化学物质的合成。

Suzuki 交叉偶联反应具有高效、高选择性和广泛的适用性，因此在药物合成、材料科学和天然产物合成等领域得到了广泛的应用。

历史Suzuki 交叉偶联反应是由日本化学家铃木敏郎于1979年首次报道的，他因此获得了2010年的诺贝尔化学奖。

铃木敏郎的研究致力于发展新的合成方法，以便更有效地合成有机化合物。

他的发现为有机合成领域带来了一种简单且高效的方法，使得复杂分子的合成变得更加容易。

反应机理Suzuki 交叉偶联反应的反应机理相对简单，其基本步骤如下： 1. 钯催化剂与有机硼试剂形成络合物； 2. 钯催化剂与有机卤化物形成络合物； 3. 钯催化剂的活化使得有机卤化物发生还原，生成活性中间体； 4. 活性中间体与有机硼试剂发生反应，形成新的碳-碳键或碳-氮键。

实验条件Suzuki 交叉偶联反应的实验条件相对温和，一般包括以下几个方面： 1. 溶剂：常用的溶剂包括乙腈、二甲基亚砜和二氯甲烷等； 2. 钯催化剂：常用的钯催化剂包括[Pd(PPh3)4]、PdCl2(PPh3)2和[Pd(PPh3)2Cl2]等； 3. 硼试剂：常用的硼试剂包括芳基硼酸和烷基硼酸等； 4. 碱：常用的碱包括碳酸钠、碳酸钾和碱金属碱等。

应用领域Suzuki 交叉偶联反应在有机合成领域具有广泛的应用，特别是在以下几个方面：1. 药物合成：Suzuki 交叉偶联反应可用于合成药物分子的关键中间体，从而提高药物的合成效率和产量； 2. 材料科学：Suzuki 交叉偶联反应可用于合成具有特定结构和性质的有机材料，如聚合物和液晶材料等； 3. 天然产物合成：Suzuki 交叉偶联反应可用于合成天然产物的关键结构单元，从而实现天然产物的全合成。

优势与挑战Suzuki 交叉偶联反应作为一种有机合成方法，具有以下几个优势： 1. 高效性：Suzuki 交叉偶联反应通常具有较高的产率和选择性，可用于合成复杂化合物； 2.适用性广泛：Suzuki 交叉偶联反应适用于不同类型的有机卤化物和硼试剂，具有较高的反应适应性； 3. 可控性强：Suzuki 交叉偶联反应可以通过调节反应条件和催化剂的选择来控制反应的速率和产物的结构。

Suzuki反应-推荐下载

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 (3)1.1 Suzuki反应的通式 (3)1.2 Suzuki反应的机理 (3)1.3 Suzuki反应的特点及研究方向 (4)2 有机硼试剂的合成 (4)2.1 通过金属有机试剂制备单取代芳基硼酸 (4)2.1.1 通过Grinard试剂制备单取代芳基硼酸示例 (4)2.1.2 通过有机锂试剂制备单取代芳基硼酸示例 (5)2.2 通过二硼烷频哪酯制备芳基硼酸酯 (6)2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一） (9)2.2.2 通过二硼烷频哪酯制备芳基硼酸酯示例（二） (10)2.2.3 通过芳基硼酸转化为芳基硼酸酯 (10)2.3 烯基硼酸酯的制备 (10)2.4 烷基硼酸酯的制备 (10)3 催化剂的制备 (11)3.1 Pd(PPh3)4的制备 (11)3.2 Pd(PPh3)2Cl2的制备 (12)3.3 Pd(dppf)Cl2的制备 (12)4Suzuki偶联的应用 (12)4.1 普通的芳卤和芳基硼酸的Suzuki偶联 (13)4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例 (14)4.2 大位阻芳基硼酸参与Suzuki偶联反应 (14)4.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应 (15)4.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联 (16)4.3.2 带着酯基底物的Suzuki偶联反应示例（一） (16)4.3.3 带着酯基底物的Suzuki偶联反应示例（二） (17)4.4 杂环芳基硼酸参与Suzuki偶联反应 (17)4.5烷基硼酸参与Suzuki偶联反应 (18)4.6烯基硼酸参与Suzuki偶联反应 (19)4.7 Triflate参与Suzuki偶联反应 (19)4.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例 (20)4.7.2 芳基的Triflate与芳基硼酸偶联示例 (20)4.8 芳基氯参与Suzuki偶联反应 (21)4.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一） (21)4.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二） (22)4.9 镍催化体系用于Suzuki偶联反应 (22)4.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例 (22)4.10 其他方法 (23)4.10.1 直接Pd/C用于Suzuki偶联反应示例 (23)4.10.2 直接Pd(OAc)2用于Suzuki偶联反应示例 (23)经典合成反应标准操作—Suzuki 反应药明康德新药开发有限公司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

文档经典化学合成反应标准操作Suzuki 反应编者：德军、武伟药明康德新药开发化学合成部目录1 前言 (3)1.1 Suzuki反应的通式 (3)1.2 Suzuki反应的机理 (3)1.3 Suzuki反应的特点及研究方向 (4)2 有机硼试剂的合成 (4)2.1 通过金属有机试剂制备单取代芳基硼酸 (4)2.1.1 通过Grinard试剂制备单取代芳基硼酸示例 (4)2.1.2 通过有机锂试剂制备单取代芳基硼酸示例 (5)2.2 通过二硼烷频哪酯制备芳基硼酸酯 (6)2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一） (9)2.2.2 通过二硼烷频哪酯制备芳基硼酸酯示例（二） (10)2.2.3 通过芳基硼酸转化为芳基硼酸酯 (10)2.3 烯基硼酸酯的制备 (10)2.4 烷基硼酸酯的制备 (10)3 催化剂的制备 (11)3.1 Pd(PPh3)4的制备 (11)3.2 Pd(PPh3)2Cl2的制备 (12)3.3 Pd(dppf)Cl2的制备 (12)4Suzuki偶联的应用 (12)4.1 普通的芳卤和芳基硼酸的Suzuki偶联 (13)4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系Suzuki偶联反应示例 (14)4.2 大位阻芳基硼酸参与Suzuki偶联反应 (14)4.3 含敏感功能团的芳基硼酸（酯）参与Suzuki偶联反应 (15)4.3.1 芳基硼酸频哪酯和芳基卤代物的Suzuki偶联 (16)4.3.2 带着酯基底物的Suzuki偶联反应示例（一） (16)4.3.3 带着酯基底物的Suzuki偶联反应示例（二） (17)4.4 杂环芳基硼酸参与Suzuki偶联反应 (17)4.5烷基硼酸参与Suzuki偶联反应 (18)4.6烯基硼酸参与Suzuki偶联反应 (19)4.7 Triflate参与Suzuki偶联反应 (19)4.7.1芳基的三氟甲基磺酸酯与芳基硼酸偶联示例 (20)4.7.2 芳基的Triflate与芳基硼酸偶联示例 (20)4.8 芳基氯参与Suzuki偶联反应 (21)4.8.1钯催化下芳基氯参与Suzuki偶联反应示例（一） (21)4.8.2钯催化下芳基氯参与Suzuki偶联反应示例（二） (22)4.9 镍催化体系用于Suzuki偶联反应 (22)4.9.1 NiCl2(dppf)和n-BuLi催化下芳基氯参与Suzuki偶联反应示例 (22)4.10 其他方法 (23)4.10.1 直接Pd/C用于Suzuki偶联反应示例 (23)4.10.2 直接Pd(OAc)2用于Suzuki偶联反应示例 (23)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。

药明康德最新笔试

大连理工2009-11-24 药明康德笔试一：写出自己的科研结果大致合成路线（简历上有可以不写，建议大家应聘时带工作总结）二：写出下列成绩：1．基础有机化学2基础有机化学3高等有机化学4有机化学试验三、1、请写出氨基和羟基的保护方法及去除方法（各至少4种）2、制备磺酰胺的方法3、形成C=C的方法4、由酸到酮的方法5、写出下列简写的结构式ClCBz NBS TEBA ………后面的记不住了啊四、写出人名反应通式（suzuki反应，Curtius 重排，Mitsunobu反应）五、写出下列合成路线及必要反应条件，及纯化方法。

（结构式记不住了）大概是一个用CBZ 保护的含氨基的大基团中的氨基与另一个大基团中的羧酸合成酰胺的条件，第二空写用四氟乙酸在DCM中脱保护的产物六、下面的化合物经过一步反应，可以分别形成10个有用的中间体，分别写出结构式2011年药明康德华中科技大学笔试试题已有14人参与1.写自己的反应的合成路线2.有机化学成绩药明康德2009年10月29日华东师大宣讲会笔试题目一：写出你在班级的排名及你获得的奖项：二：写出下列成绩：1．基础有机化学（上） 2．基础有机化学（下）3．高等有机化学（上） 4．高等有机化学（下）5．有机化学试验(上) 6．有机化学试验（下）三：写出下列反应-举例迪克曼反应；贝克曼反应：格式试剂反应：四：写出自己的科研结果大致合成路线五：选择题，立体异构选择题，其中有2个手性中心，让你填2个手性中心分别是S,R构型，然后还有三个选项让你选择与给出结构式构型一样的结构。

大概是这个结构式吧。

六：写出几个你知道的形成C-N健的反应。

七：合成。

八：画核磁1、写有机化学，高等有机化学及化学实验的成绩2、请见名扼要介绍你的毕业论文研究工作（只要用户写出合成路线即可，不需要文字描述）3、写有机反应的通式Suzuki 偶联Mannich 反应Witting 反应4、硼氢化反应中，硼烷对烯烃的加成遵守（）；在立体选择性上，硼烷对烯烃的加成是（）A 马氏规则B 反马氏规则C 顺式加成D 反式加成5、请写出至少3种将伯羟基氧化成醛的方法6、设计合成路线，从苯酚出发O H OO9 请画出一下分子的1H NMR1 写自己的科研成果，大概合成路线即可2 写出你高等有机化学和有机化学实验的成绩3 选择题选择可以作为格氏试剂的Br A 其他有含一个氧或两个氧的，记不清了~~4 Suzuki 反应和Wittig 反应通式5 完成反应 COOH NH 2(1)酰胺，Hoffman 降解Dieckmann 缩合 COOEt COOEt EtONaEtONaOH (2)6 合成Dieckmann 缩合7 画出甲酸丙酯大概的氢谱图OH O。

Suzuki–Miyaura反应

Suzuki–Miyaura反应在碱存在下有机硼试剂和芳香或烯基卤代物（或芳香三氟甲磺酸酯）在钯催化下进行交叉偶联的反应。

反应中碱的作用主要是促进金属转移。

Suzuki反应（铃木反应），也称作Suzuki偶联反应、Suzuki-Miyaura反应（铃木－宫浦反应），是一个较新的有机偶联反应，该反应由A. Suzuki 和N. Miyaura在1979年首先报道，在有机合成中的用途很广，具强的底物适应性及官能团容忍性，常用于合成多烯烃、苯乙烯和联苯的衍生物，从而应用于众多天然产物、有机材料的合成中。

铃木章也凭借此贡献与理查德·赫克、根岸英一共同获得2010年诺贝尔化学奖。

反应特点：一、反应条件温和；二、有机硼酸类化合物稳定，许多都可以直接买到；三、生成的无机物副产物都很容易除去，适合工业化生产；四、有机硼酸环境友好，毒性远低于有机锡试剂（Stille偶联反应）；五、各种官能团的底物都可以顺利进行此反应，对官能团的耐受性非常好，-CHO、-COCH3、-COOC2H5、-OCH3、-CN、-NO2、-F等官能团进行反应而不受影响，而且水不影响此反应，甚至很多条件下需要加入水作为溶剂；六、此偶联反应具有立体选择性和区域选择性，不同卤素、以及不同位置的相同卤素进行反应的活性可能有差别，三氟甲磺酸酯、重氮盐、碘鎓盐或芳基锍盐和芳基硼酸也可以进行反应，活性顺序如下：R2-I > R2-OTf > R2-Br >> R2-Cl；七、sp3-杂化的烷基硼烷也可以进行此反应【9-BBN参与的Suzuki反应实例】。

反应缺点：一、反应对氧气敏感，溶剂中溶解的少量氧气也可能导致硼酸自身偶联副产物的生成；二、反应必须在碱存在下才能进行，但是碱性条件下，一些手性底物可能会发生消旋，或者发生羟醛缩合副反应。

三、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。

下图是Suzuki反应的通式：反应催化剂此反应广泛使用的催化剂为Pd(PPh3)4与PdCl2(dppf)，其它的还有Pd(PPh3)2Cl2和NiCl2(dppf) 等等。