经典的合成反应
经典反应
人名反应1.Baeyer-Villiger氧化:酮过酸氧化成酯迁移规则：叔>仲>环己基>苄>伯>甲基>氢2.Corey-Kim 氧化:醇在NCS/DMF作用后，碱处理氧化成醛酮3.Criegee邻二醇裂解:邻二醇由Pb（OAc）4氧化成羰基化合物4.Criegee臭氧化:烯烃臭氧化后水解成醛酮5.Dakin反应:对羟基苯甲醛由碱性H2O2氧化成对二酚6.Dess－Martin过碘酸酯氧化:仲醇由过碘酸酯氧化成酮7.Fleming氧化:硅烷经过酸化，过酸盐氧化，水解以后形成醇8.Hooker氧化:2－羟基－3烷基－1，4－醌被KMnO4氧化导致侧链烷基失去一个亚甲基，同时羟基和烷基位置互变9.Moffatt氧化（Pfitzner－Moffatt）氧化:用DCC和DMSO氧化醇，形成醛酮10.Oppenauer氧化:烷氧基催化的仲醇氧化成醛酮11.Riley氧化:活泼亚甲基（羰基α位等）被SeO2氧化成酮12.Rubottom氧化:烯醇硅烷经过m－CPBA和K2CO3处理后α－羟基化13.Sarett氧化:CrO3络合物氧化醇成醛酮14.Swern氧化:用(COCl)2,DMSO为试剂合Et3N淬灭的方法将醇氧化成羰基化合物15.Tamao－Kumada氧化:烷基氟硅烷被KF，H2O2，KHCO3氧化成醇16.Wacker氧化催化剂下，烯烃氧化成酮1..Barton－McCombie去氧反应:从相关的硫羰基体中间用n－Bu3SnH，AIBN试剂经过自由基开裂发生醇的去氧作用2.Birch 还原:苯环由Na单质合液胺条件下形成环内二烯烃（带供电子基团的苯环：双键连接取代基；带吸电子基团的苯环，取代基在烯丙位。
）3.Brown硼氢化：烯烃和硼烷加成产生的有机硼烷经过碱性H2O2氧化得到醇4.Cannizzaro歧化：碱在芳香醛，甲醛或者其他无α－氢的脂肪氢之间发生氧化还原反应给出醇和酸5.Clemmensen还原：用锌汞齐和氯化氢将醛酮还原为亚甲基化合物6.Corey－Bakshi－Shibata(CBS)还原：酮在手性恶唑硼烷催化下的立体选择性还原7.Gribble吲哚还原：用NaBH4直接还原会导致N－烷基化，NaBH3CN在冰醋酸当中还原吲哚双键可以解决8.Gribble二芳基酮还原：用NaBH4在三氟乙酸中还原二芳基酮和二芳基甲醇为二芳基甲烷，也可以应用于二杂芳环酮和醇的还原9.Luche还原：烯酮在NaBH4－CeCl3下发生1，2－还原形成烯丙位取代烯醇10.McFadyen－Stevens还原：酰基苯磺酰肼用碱处理成醛11.Meerwein－Ponndorf－V erley还原：用Al（OPr’）3/Pr’OH体系将酮还原为醇12.Midland还原：用B－3－α－蒎烯－9－BBN对酮进行不对称还原13.Noyori不对称氢化：羰基在Ru（II）BINAP络合物催化下发生不对称氢化还原14.Rosenmund还原：用BaSO4/毒化Pd催化剂将酰氯氢化成醛，如催化剂未被毒化，会氢化为醇15.Wolff－Kishner－黄鸣龙还原：用碱性肼将羰基还原为亚甲基1.Boord反应：β-卤代烷氧基与Zn作用生成烯烃2.Chugaev消除：黄原酸酯热消除成烯3.Cope消除：胺的氧化物热消除成烯烃4.Corey-Winter olefin烯烃合成：邻二醇经1,1-硫代羰基二咪唑和三甲氧基膦处理转化为相应的烯5.Doering-LaFlamme丙二烯合成：烯烃用溴仿以及烷氧化物处理以后生成同碳二溴环丙烷再反应生成丙二烯6.Horner-Wadsworth-Emmons反应：从醛合磷酸酯生成烯烃.副产物为水溶性磷酸盐,故以后处理较相应的Witting反应简单的多7.Julia-Lythgoe成烯反应：从砜合醛生成(E)-烯烃8.Peterson成烯反应：从α-硅基碳负离子合羰基化合物生成烯烃.也成为含硅的Witting反应9.Ramberg-Backlund烯烃合成：Α-卤代砜用碱处理生成烯烃10.Witting反应：羰基用膦叶立德变成烯烃11.Zaitsev消除：E2消除带来更多取代的烯烃。
克莱森缩合反应
克莱森缩合反应克莱森缩合反应（ClaisenCondensation）是一种经典的有机合成反应（OrganicSynthesis），它是第一个把两个亚烷烃（Alkyne）反应，得到α,β-双键醛（α,β-Diketones）的反应。
这种反应被德国化学家Emil Hermann Fischer发现，并由他命名为克莱森缩合反应（Claisen Condensation）。
克莱森缩合反应是一种多步反应，它包含有催化剂和有机物的反应。
首先，其中一个亚烷烃被活性催化剂（Active Catalyst）如碱性金属离子如铵（Ammonium ion）、钾（Potassium）、钠（Sodium）、锂（Lithium）或碱金属氢氧化物（Alkali Metal Hydroxide）等水解，从而产生羟基腈（Hydroxycyanide），分子中的双键醛（alkene）离子（enolate ion）和碱（base）。
接下来，另一个亚烷烃（alkyne）被双键醛离子（enolate ion）活化，反应方程式如下：R-C≡C-H + RC(=O)OH R-C(=O)H + RC(=O)-C-H产物是α,β-双键醛（α,β-Diketone），可以通过进一步水解得到甲醛（aldehyde）或酮（ketone）。
克莱森缩合反应的应用也很广泛，它可以用于芳香醛的合成，也可以用于酮和醇的合成。
它还被用于合成特殊的有机分子，如吡嗪（pyridine）、吡咯（pyrrole）、氢磺化醚（thiol ether）和吡啶（pyridine）等。
克莱森缩合反应也可以用来合成药物，它可以用来合成百苯多拉丁（Bisoprolol）、等离子体低分子量肝素（Plasmolow Molecular Weight Heparin）、环苯胺（Cycloamine）、环氧乙醇（Cyclooxyethanol）和其他药物。
此外，克莱森缩合反应也可以用于分子间化学，它可以用来合成一些重要的分子，如：1、维生素A（Vitamin A）：这种维生素是一种脂溶性维生素，它可以使眼部正常发育，可以帮助皮肤正常发育，还有维持视力、健康血管和免疫功能等。
经典化学合成反应标准操作醛酮的合成
经典化学合成反应标准操作醛酮的经典合成目录1．前言 (4)2．由醇合成醛酮 (4)2.1铬（VI）试剂 (4)2.1.1 Jones氧化（Cr2O3/H2SO4/acetone） (4)2.1.2 Collins氧化（Cr2O3.2Py） (5)2.1.3 PCC（Pyrindium Chlorochromate）氧化 (8)2.1.4 PDC（Pyrindium Dichromate）氧化 (9)2.2 用活性MnO2氧化 (10)2.2.1 用活性MnO2氧化示例一: (10)2.3用DMSO氧化 (11)2.3.1 DMSO-(COCl)2氧化（Swern Oxidation） (11)2.3.2 DMSO-SO3-Pyridine (12)2.4 用氧铵盐氧化 (13)2.4.1 用氧铵盐氧化示例： (13)2.5 用高价碘试剂氧化 (14)2.5 .1 Dess-Martin氧化反应示例： (14)2.5.2 IBX氧化反应示例： (15)2.6 亚硝酸钠和醋酐氧化 (15)2.6.1 亚硝酸钠和醋酐氧化示例 (15)2.6 TPAP-NMO 氧化 (16)2.6.1 TPAP-NMO 氧化示例 (16)2.7 1,2-二醇的氧化 (16)2.7.1 1,2-二醇的氧化示例一： (17)2.7.1 其他1,2-二醇的氧化相关文献： (18)3．由卤化物合成醛酮 (18)3.1 由伯卤甲基和仲卤甲基的氧化合成醛酮 (18)3.1.1 用DMSO氧化（Kornblum反应） (18)3.1.2用硝基化合物氧化（Hass反应） (20)3.1.3用乌洛托品氧化（Sommelet反应） (21)3.1.4用对亚硝基二甲苯胺氧化吡啶翁盐氧化（Kröhnke反应） (22)3.1.5用胺氧化物氧化 (22)3.2 由二卤甲基或二卤亚甲基合成醛酮 (23)3.2.1 由二卤甲基合成醛反应示例： (23)3.3 由有机金属化合物的酰化合成醛酮 (24)3.3.1 由有机金属化合物的酰化合成醛酮示例 (25)3.4 由Pd催化反应合成醛 (25)4．由活泼甲基或活泼亚甲基烷烃合成醛酮 (25)4.1 用SeO2氧化合成醛酮 (26)4.1.1 用SeO2氧化合成醛酮示例 (26)4.2用空气氧化合成酮 (26)4.2.1用空气氧化合成酮反应示例： (27)4.3 用铬酸氧化合成酮 (27)4.3.1 用铬酸氧化合成酮示例 (27)4.4用高锰酸盐氧化合成酮 (29)4.5 用醌氧化合成酮 (29)5．由羧酸及其衍生物合成醛酮 (30)5.1由羧酸合成醛 (30)5.1.1用金属氢化物还原 (30)5.1.2由脱CO2合成醛 (31)5.1.3由羧酸合成酮 (31)5.2由酰氯及酸酐合成醛酮 (33)5.2.1用Rosenmund法合成 (33)5.2.2用金属氢化物还原 (34)5.3由酯及内酯合成醛 (35)5.3.1 酯通过DIBAL还原为醛示例： (36)5.4由酰胺合成醛酮 (36)5.4.1 由酰胺合成醛酮 (37)5.4.2 McFadyen-Stevens Reaction (38)5.5由酯或酰氯经Weinreb酰胺合成醛酮 (39)5.5.1 由Weinreb酰胺还原合成醛反应示例一 (40)5.5.2由Weinreb酰胺还原合成酮反应示例: (41)5.6由氰合成醛酮 (41)5.6.1DIBAL 还原腈到醛示例（最重要的方法） (42)5.6.2Li(EtO)3AlH 还原腈到醛示例（较重要的方法） (43)5.6.3Ranney Ni 加氢还原氰到合成醛示例 (43)5.6.4有机金属试剂对腈加成合成酮示例 (44)6. 由烯烃、芳环合成醛酮 (46)6.1 由烯烃臭氧氧化合成醛 (46)6.2 烯烃用OsO4/NaIO4氧化合成醛 (47)6.3 烯烃经由有机硼化合物中间体的烯烃甲酰化合成醛 (47)6.5 由烯烃的甲酰化合成醛 (48)6.5.1 Vilsmeyer反应 (48)6.5.2 Duff’s 甲酰化 (51)6.5.3 Reimer-Tiemann 甲酰化 (52)6.5.4 Gattermann甲酰化 (53)6.5.5 多聚甲醛/甲醇镁苯酚甲酰化 (53)6.5.6氯化锡/多聚甲醛苯酚甲酰化 (54)6.5.7重氮化后甲酰化 (54)6.6烯烃经加成-氧化反应合成酮 (56)6.6.1 烯烃经加成-氧化反应合成酮示例 (56)7. 由炔烃合成醛酮 (57)7.1 由加成-氧化反应合成醛酮 (57)7.2 由氧化反应合成酮 (57)7.3 由加成-水解反应合成酮 (58)7.4 由加成-还原反应合成酮 (59)7.5 由加成-烷基化，酰化等反应合成酮 (59)8. 由醚及环氧化合物合成醛酮 (59)8.1 Claisen重排 (59)8.2酸催化下环氧化物重排 (61)8.2.1 酸催化下环氧化物重排合成醛酮示例一 (61)8.3氧化法 (61)8.4 水解法缩醛或酮合成醛酮 (61)9. 由胺合成醛 (62)9.1胺的氧化 (62)9.1.1 胺的氧化合成醛反应示例： (63)9.2 由胺经由西佛碱的方法 (64)9.2.1 由胺经由西佛碱合成醛示例 (64)9.3 自苯胺衍生物合成 (64)10. 由硝基化合物合成醛酮 (64)11. 由Friedel-Crafts反应合成芳基酮 (65)11.1 由Friedel-Crafts反应合成芳基酮示例 (68)12. Dieckmann 缩合脱酸 (69)13. 由合成子合成醛酮 (71)14. 由砜合成醛酮 (71)15. Michael 反应和类似反应(Addition, Condensation) (71)1．前言醛和酮是一类重要的有机化合物，其合成在有机合成中占有非常重要的地位。
化学合成方法
化学合成方法化学合成方法是指通过化学反应将原料转化为所需的化合物或产物的一系列步骤和技术。
在现代化学领域，化学合成方法被广泛应用于药物研发、材料科学、催化反应等许多领域。
本文将介绍几种常见的化学合成方法，并重点介绍有机合成中的一些典型方法。
一、酸碱中和反应酸碱中和反应是一种常见的化学反应，通常用于制备水溶性的盐类。
在酸碱中和反应中，酸性物质和碱性物质反应生成盐和水。
例如，硫酸和氢氧化钠反应生成硫酸钠和水的化学方程式为：H2SO4 + 2 NaOH → Na2SO4 + 2 H2O这种方法在实验室和工业生产中广泛应用，用于制备盐类物质或调节溶液的酸碱度。
二、氧化还原反应氧化还原反应是指物质的电子转移过程，常用于氧化物和还原物的合成。
在氧化还原反应中，氧化剂接受电子，而还原剂失去电子。
典型的氧化还原反应包括金属与酸反应生成盐和气体，例如：2 HCl + Zn → ZnCl2 + H2氧化还原反应在许多有机合成中也起着重要的作用。
例如，醛和酮可以通过氧化还原反应还原为相应的醇。
三、取代反应取代反应是指分子中的一个基团被另外一个基团取代的化学反应。
取代反应广泛应用于有机合成中，可以用于合成新的化合物或改变已有化合物的结构。
取代反应的常见类型包括亲电取代、核磁取代和自由基取代等。
例如，烷烃可以通过亲电取代反应与卤代烷反应生成新的化合物。
取代反应在有机合成中具有广泛的用途和重要性，是许多药物和化学品的合成过程中不可或缺的一步。
四、合成聚合物的反应聚合物是由大量重复单元通过共价键连接而成的高聚合物化合物。
合成聚合物的反应通常涉及到单体分子之间的共价结合，形成长链的聚合物分子。
聚合反应有许多不同的类型，如自由基聚合、阴离子聚合、阳离子聚合等。
例如，苯乙烯可以通过自由基聚合反应合成聚苯乙烯，具有应用广泛的塑料材料。
合成聚合物的反应是聚合物化学中的重要领域，对于材料科学和工程应用具有重要意义。
综上所述，化学合成方法在现代化学中起着至关重要的作用。
经典合成反应操作--酮还原成亚甲基
经典合成反应操作--酮还原成亚甲基化学⽅法将醛或酮的羰基直接转化为亚甲基的⽅法有：1) Clemmensen还原；2) Wolff-Kishner-黄鸣龙还原；3) LiAlH4-AlCl3法；4) NaBH4-CF3CO2H法；5) Et3SiH-BF3或CF3CO2H法；6) HI-Phosphorus法；7) 催化氢化法。
催化氢化转化羰基为亚甲基由Brieger报导，他们使⽤Pd/C作为催化剂，并⽤FeCl3作lewis酸催化剂。
另外，有综述专门提到⽤甲酸铵作催化氢化转移剂。
哈佛的Andrew Myers在其关于腙衍⽣物⼯作中报导了⽤Sc(OTf)3作催化剂的有效的低温Wolff-Kishner还原。
对于有些结构复杂，带有多种敏感官能团时，以上这些⼀步或⼀锅法⽆法降醛或酮直接转化为亚甲基，此时可能需要降醛或酮转化为其它官能团进⾏除去。
较为常见的⽅法是转化为醇羟基除去；另外，可以将醛或酮转化为⼄⼆硫醇的缩醛或酮，再⽤Raney Ni氢化还原为亚甲基；另外，也有报导将醛或酮转化为对甲苯磺酰肼的腙，再⽤DIBAL或NaBH(OAc)3还原。
⼀、Clemmensen还原将醛或酮⽤锌汞齐处理，在浓盐酸下加热可以将醛或酮的羰基转化为亚甲基。
这就是克莱门森(Clemmensen)还原。
很明显，对酸敏感的底物(醛或酮)不能使⽤此⽅法(如醇羟基、C=C等)。
此法对于还原芳⾹酮或双烷基酮有⼀定的通⽤性。
且其⽤于还原芳⾹酮是间接在芳环上引⼊直链烃基的⽅法之⼀。
反应机理反应发⽣在锌催化剂表⾯。
由于将相应的醇⽤于此反应条件并不能得到亚甲基化合物，因此该反应中间态可能没有醇产⽣。
下图⼤致描述了克莱门森(Clemmensen)还原的机理：实例1. Clemmensen还原芳基酮于1L的圆底烧瓶中，加⼊120克锌粉、12克氯化汞、200ml⽔，5-6ml浓盐酸，振摇后将液体倒出抛弃。
随后依次加⼊75ml⽔，175ml浓盐酸，100ml甲苯，50克(0.28mol) β-苯甲酰基丙酸。
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》。
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2005-6-281•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。
经典化学反应Heck 反应-
经典化学合成反应标准操作Heck 反应目录1. 前言 (2)2. 分子内的Heck反应 (3)2.1 生成烯基取代的反应 (3)2.1.1 分子内Heck反应化生成环外双键示例 (4)2.2 形成季碳中心的反应 (5)2.2.1 分子内不对称Heck反应示例 (6)2.3 多烯大环的合成 (6)2.2.1 Heck反应用于合成大环多烯示例 (7)3. 分子间的Heck 反应 (8)3.1 常规分子间Heck反应 (8)3.1.1 Pd(OAc)2-P(o-tol)3体系用于不饱和羧酸酯的Heck反应标准操作三 (9)3.1.2 不饱和酮的Heck反应标准操作 (10)3.1.3 杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作一 (10)3.1.4 杂环芳香卤代物和不饱和羧酸酯的Heck反应标准操作二 (10)3.1.5 芳香卤代物和不饱和羧酸的Heck反应合成反式3-芳基不饱和酸示例 .. 113.1.6 非共轭双键Heck反应示例 (11)3.2 不对称分子间Heck反应 (12)3.3 非常用离去基团的Heck反应（Irina P. Beletskaya Chem. Rev. 2000, 100,3009-3066） (12)3.3.1 重氮盐参与的Heck反应示例 (13)3.3.2 酰氯参与的Heck反应示例 (15)1. 前言通常把在碱性条件下钯催化的芳基或乙烯基卤代物和活性烯烃之间的偶联反应称为Heck反应。
自从20世纪60年代末Heck 和Morizoki独立发现该反应以来,通过对催化剂和反应条件的不断改进使其的应用范围越来越广泛,使该反应已经成为构成C-C键的重要反应之一。
另外，Heck反应具有很好的Trans选择性R XPd(0)Z RZX = I, Br, OTf, etcZ = H, R, Ar, CN, CO2R, OR, OAc, NHAc, etc研究表明，Heck反应的机理有一定的规律，通常认为反应共分四步：（a）氧化加成（Oxidative addition）: RX (R为烯基或芳基，X=I > TfO > Br >> Cl)与Pd0L2的加成，形成PdⅡ配合物中间体；（b）配位插入（Cordination-insertion）:烯键插入Pd-R键的过程；（c）β-H的消除；（d）催化剂的再生：加碱催化使重新得到Pd0L2。
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,-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。
化学反应大全
化学反应大全化学反应是化学领域中最基本的研究对象之一，它描述了不同物质之间发生的变化过程。
本文将介绍一些常见的化学反应类型和实例，让读者对化学反应有更全面的了解。
一、酸碱中和反应酸碱中和反应是指发生在酸和碱之间的反应，常常产生盐和水。
例如：HCl + NaOH → NaCl + H2O二、氧化还原反应氧化还原反应是指物质中电子的转移过程。
氧化剂接受电子，而还原剂失去电子。
下面是一个经典的氧化还原反应实例：2Na + Cl2 → 2NaCl三、合成反应合成反应是指两个或多个物质反应形成一个新的物质。
例如：2H2 + O2 → 2H2O四、分解反应分解反应是指一个物质分解成两个或多个新的物质。
例如：2H2O → 2H2 + O2五、置换反应置换反应是指一个元素或基团被另一个元素或基团替代的反应。
例如：Zn + CuCl2 → ZnCl2 + Cu六、酯化反应酯化反应是指酸和醇反应生成酯的反应。
例如：CH3COOH + C2H5OH → CH3COOC2H5 + H2O七、水解反应水解反应是指化合物在水的作用下被分解成其他物质的反应。
例如：C12H22O11 + H2O → C6H12O6 + C6H12O6八、酸催化反应酸催化反应是指在酸的存在下，化学反应速率加快的过程。
例如：C2H5OH + H2SO4 → C2H5OH2+ + HSO4-九、废气处理反应废气处理反应是指将有害气体转化为无害物质的反应。
例如：2NO2 + H2O → HNO3 + HNO2十、光合作用反应光合作用反应是指植物中利用光能将二氧化碳和水转化为有机物的反应。
例如：6CO2 + 6H2O → C6H12O6 + 6O2以上十种化学反应只是众多反应中的一小部分，每一种化学反应都有其独特的特点和应用。
通过学习和理解这些化学反应，我们可以更好地掌握化学知识，应用于各个领域，例如工业、医药和环境保护等。
总结：化学反应是化学领域中的重要内容之一，通过研究和理解不同类型的化学反应，我们可以更好地应用于实际生活和工作中。
williamson醚合成反应
williamson醚合成反应
Williamson醚合成反应是一种通过将一种醇和一种卤化烃反应生成醚的方法。
它是一种经典的有机化学合成反应，由英国化学家亨利·威廉姆森于1850年首次提出。
反应机理：首先，卤代烃在碱催化下形成亲核性碳阴离子，然后亲核性碳阴离子攻击醇中的亲电性氧原子，生成醚，并释放出一分子卤化氢。
反应方程式：R-OH+R'-X→R-O-R'+HX。
其中，R和R'可以是相同或不同的烷基或芳基基团，X是卤素原子（如氯、溴或碘），HX是卤化氢酸。
该反应在室温下进行，通常在碱性条件下进行，如氢氧化钠（NaOH）或氢氧化钾（KOH）溶液中，以提高反应速率。
而且，由于亲核性碳阴离子的生成需要碱催化，因此醇中必须存在能够失去质子并形成碳阴离子的氢原子。
Williamson醚合成反应广泛应用于制备各种醚，从简单的芳香族醚到复杂的天然产物和多环化合物。
铁催化合成氨反应机理
铁催化合成氨反应机理
铁催化合成氨反应是一种经典的合成氨反应，其反应机理主要包括以下步骤：
1. 吸附：氢气和氮气在铁催化剂表面吸附，形成表面氢化物和氮化物。
2. 解离：吸附在催化剂表面的氢气和氮气通过解离成原子，形成活性氢和活性氮。
3. 合成：活性氢和活性氮通过铁催化剂表面的活性位点进行合成，生成氨分子。
4. 脱附：生成的氨分子从催化剂表面脱附，完成合成氨反应。
具体反应过程如下：
N2(g)+6H2(g)→2NH3(g)
在反应过程中，铁催化剂表面的晶格缺陷、氧化还原状态以及表面酸碱性等都会对反应速率和产物选择性产生影响。
同时，反应条件如温度、压力、气体流量等也会对反应过程产生重要影响。
需要注意的是，铁催化合成氨反应是一个复杂的过程，其实际反应机理可能比上述简单描述更为复杂。
在实际应用中，需要综合考虑各种因素，通过实验和模拟研究来深入了解反应机理，优化反应条件和催化剂制备工艺，以提高反应效率和产物选择性。
醇酸树脂合成反应方程式
醇酸树脂合成反应方程式
醇酸树脂合成反应方程式
醇酸树脂是由多元醇、多元酸和一元酸聚合而成的一种树脂。
其合成反应包括醇解反应、缩聚反应、醇-异氰酸反应和酸催化醇酸缩合反应。
1. 醇解反应
醇解反应是合成醇酸树脂的重要反应之一。
该反应通常在酸催化下进行，多元醇和多元酸在一定温度和压力下进行酯化反应，生成中间产物酯。
n ROH + n R'COOH → (R-O-R')n + n H2O
其中，R代表醇的烃基，R'代表酸的烃基，n表示聚合度。
2. 缩聚反应
缩聚反应是醇酸树脂合成的重要步骤之一。
在该反应中，多个单体分子通过缩合反应形成大分子链。
同时，脱去小分子化合物（如水、醇等）。
n R-OH + n R'-COOH → (R-O-R')n + n H2O
3. 醇-异氰酸反应
醇-异氰酸反应是合成高聚物的重要反应之一。
在该反应中，醇与异氰酸反应生成聚氨酯。
n ROH + n OCNHR' → (R-O-CNHR')n + n H2O
4. 酸催化醇酸缩合反应
酸催化醇酸缩合反应是合成醇酸树脂的经典反应之一。
在该反应中，多元醇和多元酸在酸性催化剂的作用下进行缩合反应，生成醇酸树脂。
n ROH + n R'COOH → (R-O-R')n + n H2O
其中，R代表醇的烃基，R'代表酸的烃基，n表示聚合度。
二氯亚砜与甲酸的反应条件
二氯亚砜与甲酸的反应条件
二氯亚砜与甲酸的反应是一种经典的有机合成反应，通常用于合成甲砜酸。
以下将详细介绍该反应条件及机理。
反应条件：
1.反应物的纯度要求较高，通常要求二氯亚砜和甲酸的纯度在99%以上。
2.反应通常在无水和无氧的条件下进行，因为二氯亚砜和甲酸都容易受到水和氧的影响而分解。
3.反应温度一般在室温下进行，但也可在低温条件（-10~0℃）下进行以控制反应速率。
4.通常需要一定时间的反应，在常温下反应时间一般为12小时以上。
反应机理：
二氯亚砜与甲酸的反应机理主要存在两个可能的途径：
途径一：
1.二氯亚砜中的Cl原子相对活泼，首先与甲酸中的氢原子发生单
质的反应，生成盐酸和甲砜。
2.接着，甲酸的二氧化碳部分与二氯亚砜反应生成碳酸二氯亚砜，同时释放出CO2。
3.最后，碳酸二氯亚砜和甲砜再次反应生成甲砜酸和二氯亚砜。
途径二：
1.二氯亚砜的不饱和氧硫键发生亲电进攻，形成临时的正离子中
间体，同时释放出Cl-。
2.甲酸的甲基基团通过亲核取代反应攻击中间体的硫原子。
3.随后，中间体失去一个Cl-离子，生成甲砫盐。
4.最后，通过脱氯反应，甲砫盐与氢氧化钠反应脱氯生成甲砜酸，并再生二氯亚砜。
综上所述，二氯亚砜与甲酸反应的机理较为复杂，可能存在多种
反应途径。
其实际所需条件较为严苛，需要保证反应物品质纯净且无
水无氧，同时在恰当的温度下进行，才能获得较好的反应效果。
理解该反应的条件和机理，有助于合理地设计和优化该反应的实验流程。
克莱森-施密特反应的应用
克莱森-施密特反应的应用一、引言克莱森-施密特反应，作为有机化学中的一种重要反应，自发现以来一直在合成化学领域发挥着重要作用。
该反应以其独特的反应机制和广泛的应用范围，成为许多化学领域研究者和工业界关注的焦点。
本文将深入探讨克莱森-施密特反应的原理及其在各个领域中的应用，以期为相关研究和工业生产提供有价值的参考。
二、克莱森-施密特反应的原理简介克莱森-施密特反应，又称为克莱森酯缩合反应，是指在酸催化剂的作用下，两个酯类化合物进行缩合反应，生成一个β-酮酸酯类化合物和一个醇类化合物的反应。
该反应的关键步骤是形成一个新的碳碳键，同时伴随着酯基的迁移。
这一过程涉及电子和质子的转移，为有机化学合成提供了丰富的手段。
三、克莱森-施密特反应的应用领域1.药物合成：许多药物分子中包含β-酮酸酯结构，克莱森-施密特反应在药物合成中发挥了重要作用。
通过该反应，可以高效地合成具有特定结构的药物中间体，为药物研发提供了便利。
2.天然产物合成：自然界中存在许多具有生物活性的化合物，其结构中包含β-酮酸酯片段。
利用克莱森-施密特反应，可以模拟自然界中的合成过程，高效地合成这些具有生物活性的化合物。
3.材料科学：在材料科学领域，克莱森-施密特反应被用于合成功能性材料，如聚合物、涂料和纤维等。
这些材料在电子、光学和生物医学等领域具有广泛的应用前景。
4.组合化学：组合化学中，克莱森-施密特反应可用于构建和筛选化合物库。
通过在反应过程中引入不同的取代基团，可以快速生成大量具有不同结构的化合物，为新药发现和材料探索提供有力支持。
5.有机合成方法学：克莱森-施密特反应作为一种经典的有机合成方法，不断被优化和改进。
通过研究该反应与其他反应的串联过程，可以发展出新的有机合成方法，简化复杂化合物的合成路线。
四、未来展望随着科学技术的发展，克莱森-施密特反应在未来的研究和应用中仍有广阔的发展空间。
以下是对其未来发展的展望：1.绿色合成路径：目前，许多克莱森-施密特反应仍使用传统的酸催化剂，这可能带来环境污染问题。
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Boc脱保护-------------------------------------------------------------------------------------------------------1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---------------------------------------------------------------------------------------------------------------5 氢化反应---------------------------------------------------------------------------------------------------------6 m-CPBA----------------------------------------------------------------------------------------------------------6 EDC---------------------------------------------------------------------------------------------------------------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 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. To this solution ofethylmagnesium 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), 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, 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).Return Suzuki 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 °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) 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 HOOOA 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 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, 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. 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 HOHOA 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 isrecrystallized 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NNHOOH 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).ReturnNBSN NFClCl NBSNNFClClBrA 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 wasallowed 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 2NHN 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 mixturewas 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 F FFN O O+F FF ONFTo a solution of diisopropylamine (17.69 ml, 0.135 mole) in THF (200 ml) at –78°C under argon wasadded 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。
有机合成反应经典反应 Suzuki反应
经典化学合成反应标准操作1 前言 ................................................................................................................... 21.1 Suzuki 反应的通式........................................................................................ 2 1.2 Suzuki 反应的机理........................................................................................ 2 1.3 Suzuki 反应的特点及研究方向 ...................................................................... 32 有机硼试剂的合成 ........................................................................................... 32.1 通过金属有机试剂制备单取代芳基硼酸 ........................................................ 3 2.1.1 通过 Grinard 试剂制备单取代芳基硼酸示例 ............................................... 3 2.1.2 通过有机锂试剂制备单取代芳基硼酸示例 .................................................... 4 2.2 通过二硼烷频哪酯制备芳基硼酸酯 ............................................................... 5 2.2.1 通过二硼烷频哪酯制备芳基硼酸酯示例（一）............................................ 8 2.2.2 通过二硼烷频哪酯制备芳基硼酸酯示例（二）............................................ 9 2.2.3 通过芳基硼酸转化为芳基硼酸酯 .................................................................... 9 2.3 烯基硼酸酯的制备 ....................................................................................... 9 2.4 烷基硼酸酯的制备 ....................................................................................... 93 催化剂的制备 ................................................................................................. 103.1 Pd(PPh3)4 的制备 ........................................................................................ 10 3.2 Pd(PPh3)2Cl2 的制备 .................................................................................... 11 3.3 Pd(dppf)Cl2 的制备 ..................................................................................... 114 Suzuki 偶联的应用 ...................................................................................... 114.1 普通的芳卤和芳基硼酸的 Suzuki 偶联 ........................................................ 12经典合成反应标准操作—Suzuki 反应4.1.1 Pd(PPh3)4-Na2CO3-DME-H2O 体系 Suzuki 偶联反应示例 .................... 13 4.2 大位阻芳基硼酸参与 Suzuki 偶联反应 ........................................................ 13 4.3 含敏感功能团的芳基硼酸（酯）参与 Suzuki 偶联反应 ................................ 14 4.3.1 芳基硼酸频哪酯和芳基卤代物的 Suzuki 偶联 ............................................ 15 4.3.2 带着酯基底物的 Suzuki 偶联反应示例（一） ............................................ 15 4.3.3 带着酯基底物的 Suzuki 偶联反应示例（二） ............................................ 16 4.4 杂环芳基硼酸参与 Suzuki 偶联反应 ............................................................ 16 4.5 烷基硼酸参与 Suzuki 偶联反应 ................................................................... 17 4.6 烯基硼酸参与 Suzuki 偶联反应 ................................................................... 18 4.7 Triflate 参与 Suzuki 偶联反应 ..................................................................... 18 4.7.1 芳基的三氟甲基磺酸酯与芳基硼酸偶联示例............................................... 19 4.7.2 芳基的 Triflate 与芳基硼酸偶联示例 ........................................................... 19 4.8 芳基氯参与 Suzuki 偶联反应 ...................................................................... 20 4.8.1 钯催化下芳基氯参与 Suzuki 偶联反应示例（一） ..................................... 20 4.8.2 钯催化下芳基氯参与 Suzuki 偶联反应示例（二） ..................................... 21 4.9 镍催化体系用于 Suzuki 偶联反应 ............................................................... 21 4.9.1 NiCl2(dppf)和 n-BuLi 催化下芳基氯参与 Suzuki 偶联反应示例 ............... 21 4.10 其他方法 ................................................................................................. 22 4.10.1 直接 Pd/C 用于 Suzuki 偶联反应示例 ...................................................... 22 4.10.2 直接 Pd(OAc)2 用于 Suzuki 偶联反应示例 ............................................... 22Page 1 of 24经典合成反应标准操作—Suzuki 反应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。
傅克酰基化反应 文档
傅克酰基化反应文档傅克酰基化反应是一种重要的有机合成反应，通常指酚和羧酸酯之间的酯化反应。
该反应是一种经典的羧酰基化反应，可以在实验室中进行，也可以工业上进行大规模生产。
其应用范围十分广泛，主要用于有机合成、医药化学、农药合成、材料科学等领域。
傅克酰基化反应的机理可以分为两步，第一步是酯化反应，酸性质子（H+）与羧基的氧原子脱去水分子，生成羧酰衍生物的反应，它是一个平衡反应，所以利用过多的酯和水来推动反应向右移动平衡。
第二步是脱酸反应，通过加入鹼，使酸当中的甲基水解并结合表面，形成CH3OH，并进一步再加上水，生成醇类和羧酸衍生物。
傅克酰基化反应一般是在弱酸性条件下进行，很少使用较强的有机酸，如硫酸等。
主要有以下几种方法：1. 环状酯化反应：具有环状结构的羧酸可以通过环状酯化反应与醇建立酯键。
该方法中羧酸与醇的反应速率很快，可在常温常压下进行。
2. 磺酸盐酯化反应：用磺酸盐作为反应催化剂，将酯成分直接与酚部分反应生成酯。
它具有催化速率快、反应条件温和等优点，适用于大规模工业生产。
3. 酸催化剂酯化反应：酸催化剂如三氟化硼、五氟化磷会吸引电子，增强酯基的亲电性，从而使反应更容易进行。
该方法操作简便、效果明显、成本低，适用于实验室规模的反应。
4. 催化酯化反应：酯化催化剂可以采用多种材料，如金属催化剂、封闭酚环的新型离子催化剂、嫁接酚基的均聚体催化剂和酰氯催化剂等。
其中金属催化剂表现出良好的催化活性和选择性，但催化通常需要高温和高压。
傅克酰基化反应也有一些局限性，如在过多的水的存在下，反应会变慢甚至停止，同时酯化反应的平衡性也会影响到反应的效率，因此需要优化反应条件，调节反应中各组分的平衡关系，以提高反应的产率。
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经典的合成反应一、 卤化反应 （一） 卤加成反应 1. 卤素的加成 1）烯烃X 2CC XX 2=Cl 2, Br 2机理c c c c c c ｘ ｘR 1R R 34R 1R 4R 334R R ①ｘ-R 1R 4R 3R 34R R 1②+c c c c δ-加硼烷CH 3-CH=CH 2BH 3(CH 3-CH 2-CH 2)3B23CH 3CH 2CH 2Br反马氏产物C 6H 13C CHBH O 70℃,2hC CC 6H 13HHO B 25℃,2hC CC 6H 13HH2C CC 6H 13HHI90%I 2/NaOH/H 2O 2H 2O3）不饱和羧酸 2. 卤化氢的加成加卤化氢H X C C H X =H C l, H B r, HI机理C R1R3+C R2C R2HH反向同向CH 3CH=CH 2CH 3CHBrCH 3CH 3CH 2CH 2BrMarkovnikov 加成反Markovnikov 加成Ph-CH=CH 2HBrHBr H 2O 2或光照Ph--C-CH 3Ph-CH 2CH 2Br Br反马氏规则3. 次卤酸（酯）、N-卤代酰胺加成C CX 2CCX+H 2OHXX 2=Cl 2, Br 2+（二） 卤代反应 1.烃类 1）脂肪烃芳烃卤代反应 机理+E+Eπ-络合物HEE +H +σ-络合物HX X-H ++-σ-络合物举例：Cl CH 3+CH 3CH 3CH 3CH 3CH 3BrClBr ++22OHOHBr°0 COH BrBr BrH 2O 2H 2O 2Br 22Br 2/Bu-NH 2-70 COHBrBr OHBrBr °OHOHOH2.羰基化合物羰基化合物的卤代反应机理OR R'δδCC OHB C COBHCOC COC C C等于C OHCOO HC OCHCOCH1）醛、酮酮α-H 卤代反应R- C - CH 3OR- C - CH 2BrO2亲电取代反应C CHCCC COC CH OHOH酸催化机理C C H OH慢C C C C X碱催化机理举例：O 2NC-CH 3O O 2N C-CH 2BrOHBrBr 2+氯霉素的制备溴对酮的加成CH 2CH 2CHH 2C OHC CHCH 2CH 33COHCH 2CH 23BrH 2C OCH 2CH 2CH 3H Br HBr-Br 2C CH 2CH 2CH 32C OCHCH 2CH 3H 3C OBr+(1.5%)(58%)酮自由基反应(饱和烃、苄位和烯丙位的卤取代反应、某些不饱和烃的卤加成反应以及羧基、重碳基的卤置换反应)α-羰基自由基取代OCC O R'H R''R'''+Br2+CC OR'Br R''R'''Br 22Br光O +HBrOHBrO O O OBrBr CHOCHO Br2）羧酸衍生物 3.醇、酚、醚 1）醇 2）酚 3）醚4.羧酸1）羧羟基2）羧酸脱羧5.其他官能团的卤代反应1）卤化物2）磺酸酯3）芳香重氮盐化合物二、烃化反应（一）碳原子的烃化反应1.芳烃的烃化Friedel-Crafts 烷基化反应芳烃与卤代烃、醇类或烯类化合物在Lewis催化剂(如AlCl3，FeCl3, H2SO4, H3PO4, BF3, HF等)存在下，发生芳环的烷基化反应。
卤代烃反应的活泼性顺序为：RF > RCl > RBr > RI ; 当烃基超过3个碳原子时，反应过程中易发生重排。
反应机理首先是卤代烃、醇或烯烃与催化剂如三氯化铝作用形成碳正离子：所形成的碳正离子可能发生重排，得到较稳定的碳正离子：碳正离子作为亲电试剂进攻芳环形成中间体s-络合物，然后失去一个质子得到发生亲电取代产物：反应实例2. 羰基化合物的a 位C 烃化1．活泼亚甲基化合物的C-烃化H 2CX YX, Y 为吸电子基吸电子能力：-NO 2 ＞-CR ＞ RSO 2-＞- CN ＞-COOR ＞ Ph OCH 2COOEtCOOEtC OOOEt OEtHCC C OOEtOOEtR-HCC OOOEtOEt+ BHR-Xδδ反应机理：2. 醛酮以及羧酸衍生物α-C 烃化-C OCHROCX Y活性小于活泼亚甲基化合物反应式-C OCH-C OC-C OCR反应机理-C OCHO-C OOCR+ HX影响因素：碱: 三苯甲基钠(锂)Ph 3CNa, 丁基锂NaH 、NaNH 2二异丙基氨基锂 (i-Pr)2NLi环己基异丙基氨基锂NLi(i-Pr)23. 其他碳原子的烃化Koble 反应脂肪酸钠盐或钾盐的浓溶液电解时发生脱羧，同时两个烃基相互偶联生成烃类：如果使用两种不同脂肪酸的盐进行电解，则得到混合物：反应机理反应实例4. 有机金属化合物在C-烃化中的应用 （二） 氧原子上的烃化反应 1. 醇1. 卤代烷为烃化剂 反应机理一R-X R X+决定反应速率R +R'OHR-O-R'快+HPh-CH 2X R-CH=CH-CH 2X 叔卤代烷、、按SN1历程反应机理二R'OCXRHR'O+R-CH 2-XR'O-CH 2R +X构型翻转从X 的背面进攻2. 磺酸酯 (CH 3)2SO4 , (C 2H 5)2SO 4SO 3R SO 3RH 3CTsO 很好的离去基团SO O1 2CH 3OH+H 2SO(CH 3)2SO 4+2H 2O制备方法:2CH 3OHNaCl H 2O SO 3Cl3SO 3CH 33+++,,3.环氧乙烷类作烃化剂CH HCR HOHb NuC R HCH 2-OH+H +CH HCR HH ONaRCH-CH 2OH+反应实例OOH OCH 3CH OH/H +80%△Ph-CH-CH 2+EtOHNaOHCH 3CHCH 2OEtOH80%Ph-CH-CH 2PHCHCH 2OCH3OHPH-CHCH 2OHOCH 3+CH 3OH+PhCHCH 2OH 310%90%PHCHCH 2OCH 3OH+75%25%4.烯烃作为烃化剂R-OH + CH 2=CH-R δδ烯烃反位的R 为吸电子基醇对烯烃双键进攻，加成而生成醚。
烯烃结构中若无极性基团存在，反应不易进行；只有当双键两端连有吸电子基，才能反应。
吸电子基：C O-CN -COOR'-COOHCH 3CH=CHCHC 3H 7OH+OOH 3C C 3H 7OCHCH 2-CH45%CH 3+CH 2=CHCN3CH 3OCH 2CH 2CNOHHO CH 2=CHCN 2OCH2CH 2CNHOH +水解OHOO-CN5.醇作为烃化剂醇：通常加酸作为催化剂，如 H 2SO 4 H 3PO 4 TsOH HCl 气体HOCH 2CH 2CHCH 2OHTsOHOH△OOH88%ClCHCN C 2H 54924甲苯 回流COClC CC 2H 5OC 4H 9CN6.其它烃化剂CF 3SO 2OR-SO 3RR 3O BF 4用来烃化位阻醇2. 酚（三） 氮原子上的烃化反应 1. 氨及脂肪胺RX+NH H 3N C XRNH 3X RNH 2+NH 4XNH RX+RNH 2R 2NH 2X R 2NH+NH 4X NH RX+R 2NH R 3NHX R 3N+NH 4XNH RX+R 3NR 4NX1.伯胺的制备Gabriel 合成法邻苯二甲酰亚胺与氢氧化钾的乙醇溶液作用转变为邻苯二甲酰亚胺盐，此盐和卤代烷反应生成N-烷基邻苯二甲酰亚胺，然后在酸性或碱性条件下水解得到一级胺和邻苯二甲酸，这是制备纯净的一级胺的一种方法。
有些情况下水解很困难，可以用肼解来代替：反应机理邻苯二甲酰亚胺盐和卤代烷的反应是亲核取代反应，取代反应产物的水解过程与酰胺的水解相似。
反应实例2.芳香胺及杂环胺（四）保护反应1.羟基的保护2.氨基的保护（五）相转移烃化反应1.碳烃化2.氧烃化3.氮烃化三、酰化反应（一）碳原子的酰化反应1．活性亚甲基化合物2. 烯烃、烯胺的酰化3. 芳烃碳的酰化Friedel-Crafts 酰基化反应芳烃与酰基化试剂如酰卤、酸酐、羧酸、烯酮等在Lewis酸(通常用无水三氯化铝)催化下发生酰基化反应，得到芳香酮：这是制备芳香酮类最重要的方法之一，在酰基化中不发生烃基的重排。
反应机理反应实例（二）氧原子的酰化反应1. 醇羟基氧的酰化2. 酚羟基（三）氮原子的酰化反应氮原子的酰化（四）保护反应1. 醇、酚的保护2. 氨基的保护四、缩合反应（一）a羟烷基、卤烷基、氨烷基化反应1. a羟烷基Darzen反应反应机理：制备a,b－环氧酸酯：氯代酸酯在醇钠的作用下，与醛酮发生反应得到再温和的条件下水解脱羧得烯醇式结构，最后异构化为增加一个碳的醛。
反应实例：由b-紫罗兰酮与氯乙酸乙酯制备维生素A的中间体2. 卤烷基3. 氨烷基（二）β羟烷基、β羰烷基1. β羟烷基2. β羰烷基（三）亚甲基化反应1. 羰基烯化2. 羰基a-亚甲基化反应Claisen 酯缩合反应含有α-氢的酯在醇钠碱性缩合剂作用下发生缩合作用，失去一分子醇得到β-酮酸酯。
如2分子乙酸乙酯在金属钠和少量乙醇作用下发生缩合得到乙酰乙酸乙酯。
二元羧酸酯的分子内酯缩合见Dieckmann缩合反应。
反应机理乙酸乙酯的α-氢酸性很弱（pK a-24.5),而乙醇钠又是一个相对较弱的碱（乙醇的pK a~15.9），因此，乙酸乙酯与乙醇钠作用所形成的负离子在平衡体系是很少的。
但由于最后产物乙酰乙酸乙酯是一个比较强的酸，能与乙醇钠作用形成稳定的负离子，从而使平衡朝产物方向移动。
所以，尽管反应体系中的乙酸乙酯负离子浓度很低，但一形成后，就不断地反应，结果反应还是可以顺利完成。
常用的碱性缩合剂除乙醇钠外，还有叔丁醇钾、叔丁醇钠、氢化钾、氢化钠、三苯甲基钠、二异丙氨基锂（LDA)和Grignard试剂等。
反应实例如果酯的α-碳上只有一个氢原子，由于酸性太弱，用乙醇钠难于形成负离子，需要用较强的碱才能把酯变为负离子。
如异丁酸乙酯在三苯甲基钠作用下，可以进行缩合，而在乙醇钠作用下则不能发生反应：两种不同的酯也能发生酯缩合，理论上可得到四种不同的产物，称为混合酯缩合，在制备上没有太大意义。
如果其中一个酯分子中既无α-氢原子，而且烷氧羰基又比较活泼时，则仅生成一种缩合产物。
如苯甲酸酯、甲酸酯、草酸酯、碳酸酯等。
与其它含α-氢原子的酯反应时，都只生成一种缩合产物。
实际上这个反应不限于酯类自身的缩合，酯与含活泼亚甲基的化合物都可以发生这样的缩合反应，这个反应可以用下列通式表示：Dieckman缩合反应－分子内的Claisen缩合二元羧酸酯Michael 加成反应一个亲电的共轭体系和一个亲核的碳负离子进行共轭加成，称为Micheal 加成：反应机理反应实例Knoevenagel 反应含活泼亚甲基的化合物与醛或酮在弱碱性催化剂(氨、伯胺、仲胺、吡啶等有机碱)存在下缩合得到a,b-不饱和化合物。