Review of Chapter 3 Email: mengge@mail.xjtu.edu.cn Tel: 82656327(o), 15877657967(m) http://gr.xjtu.edu.cn:8080/web/mengge April, 17, 24, 27,2012

Acylation Methods Acylation on O: Esters Acylation on N: Amides Acylation on C: Ketones or aldehydes F-C Hoesch Formylation Gattermann (Special Hoesch) Vilsmeier-Haack Reimer-Tiemann Hoesch反应： 酚或酚醚在氯化氢和氯化锌等Lewis酸的存在下，与腈作用后水解，得到酰基酚或酰基酚醚. 腈类化合物与氯化氢在Lewis酸催化剂ZnCl2的存在下，与具有羟基或烷氧基的芳烃(酚或酚醚)进行反应可生成相应的酮亚胺(ketimine)，再经水解则得具有羟基或烷氧基的芳香酮(酰基酚或酰基酚醚)，称之为Hoesch反应.

Gattermann reaction The Gattermann reaction refers to a reaction of hydrocyanic acid with an aromatic compound, in this case benzene, under catalysis with Friedel-Crafts catalyst (aluminum chloride). The reaction is similar to the Friedel-Crafts reaction. Gattermann甲酰化反应 具有羟基或烷氧基的芳香烃在催化剂(AlCl3或ZnCl2)的存在下和氰化氢及氯化氢作用生成芳香醛的反应称为Gattermann甲酰化反应。

Vilsmeier-Haack reaction The Vilsmeier-Haack reaction (also called the Vilsmeier reaction) is the chemical reaction of a substituted amide with phosphorus oxychloride and an electron-rich arene to produce an aryl aldehyde or ketone. The reaction of a substituted amide with phosphorus oxychloride gives a substituted chloroiminium ion, also called the Vilsmeier reagent. The initial product is an iminium ion, which is hydrolyzed to the corresponding aromatic ketone or aldehyde during workup.

Reimer-Tiemann reaction The Reimer-Tiemann reaction is a chemical reaction used for the ortho-formylation of phenols. salicylaldehyde Chloroform reacts with strong base to form dichlorocarbene, which will react in the ortho-position of the phenate to give the dichloromethyl substituted phenol. After basic hydrolysis, the product is formed.

Synthesis of aromatic aldehydes Other Formylation Methods: Duff reaction Functional group transformation Sommelet reaction Kröhnke aldehyde synthesis reaction Oxidation (Chapter 6) Swern oxidation PCC oxidation CAN SeO2 Etard reaction monooxidation Reduction (Chapter 7) From carboxylate derivatives via metal hydride reduction Rosenmund reduction

Chapter 4 Condensation Reaction 第四章 缩合反应 本章主要讨论内容： 具有活泼氢的化合物与羰基化合物之间的缩合反应 用途：形成新的碳-碳键或碳-杂键

Definition of Condensation Reaction A condensation reaction is a chemical reaction in which two molecules or moieties (functional groups) combine to form one single molecule, together with the loss of a small molecule. When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride, methanol, or acetic acid. The word "condensation" suggests a process in which two or more things are brought "together" (Latin "con") to form something "dense", like in condensation from gaseous to liquid state of matter; this does not imply, however, that condensation reaction products have greater density than reactants. 两个及两个以上有机化合物分子通过反应，失去一个小分子，形成一个新的较大分子；或同一分子发生分子内反应，失去一个小分子，形成新分子的反应，也称为缩合反应。

Intermolecular and intramolecular Intermolecular：When two separate molecules react, the condensation is termed intermolecular. A simple example is the condensation of two amino acids to form the peptide bond characteristic of proteins. This reaction example is the opposite of hydrolysis, which splits a chemical entity into two parts through the action of the polar water molecule, which itself splits into hydroxide and hydrogen ions. If the union is between atoms or groups of the same molecule, the reaction is termed intramolecular condensation, and in many cases leads to ring formation. An example is the Dieckmann condensation, in which the two ester groups of a single diester molecule react with each other to lose a small alcohol molecule and form a β-ketoester product.

Section Iα-Functionalized alkylation α-羟烷基化反应 (-hydroxyalkylation) Aldol condensation, Prins, Benzoin,etc. α-卤烷基化反应 (-chloroalkylation) Blanc reaction, α-氨烷基化反应 (-aminoalkylation) Mannich, Pictet-Spengler, Strecker,etc.

1.1 -hydroxyalkylation 醇醛(酮)缩合 不饱和烃的-羟烷基化反应 芳醛的-羟烷基化反应(安息香缩合) (Aldol condensation) 不饱和烃的-羟烷基化反应 (Prins reaction) 芳醛的-羟烷基化反应(安息香缩合) (Benzoin condensation) 有机金属化合物的-羟烷基化 (-hydroxyalkylation): Reformatsky reaction

1.1.1 醇醛缩合反应 (Aldol condensation) 1.1.1 醇醛缩合反应 (Aldol condensation) Definition: An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone. 定义：含有α-H的醛或酮，在稀碱或稀酸(通常为稀碱)的催化作用下，一分子醛(或酮)的-氢原子加到另一分子醛(或酮)的氧原子上，其余部分加到羰基碳上，生成β-羟基醛(或酮)的反应，该增长碳链的反应称为醇(羟)醛(酮)缩合反应。

Formation of conjugated enone Aldol condensations are important in organic synthesis, providing a good way to form carbon–carbon bonds. It involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or “aldol” (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals. Reaction mechanisms

Mechanism A：Base catalyzed Inorganic Base: NaOH, Na2CO3, NaH, etc. Organic Base: EtONa, BuLi, etc.

Mechanism B：Acid catalyzed Acid: H2SO4, HCl, TsOH, etc.

1.1.1.1 Self-Condensation between two same molecules 一般用碱性催化剂

Synthesis of 2-Ethyl Hexanol Application： Synthesis of 2-Ethyl Hexanol 异辛醇 Target Molecules: iso-octyl alcohol

甲醛与含α-H醛酮的多伦缩合反应 (羟甲基化) 1.1.1.2 Hetero-Condensation between different molecules a. Tollens condensation (hydroxymethylation) 甲醛与含α-H醛酮的多伦缩合反应 (羟甲基化) 含有-氢的醛或酮在Ca(OH)2、K2CO3、NaHCO3等碱的存在下，用甲醛处理，在醛、酮的-碳原子上引入羟甲基的反应称为Tollens condensation reaction。 不含 α-氢原子的甲醛和含有α -氢的醛（或酮）类在或碱性催化剂存在下制造多元醇类的方法。由德国化学家多伦斯于1891年所创始。本反应实际上由*醇醛缩合和交叉坎尼札罗反应结合而成。 This reaction involves the condensation of formaldehyde with an aliphatic aldehyde having an a-hydrogen, followed by a crossed Cannizzaro reaction to produce geminal bishydroxymethyl derivatives. It is a commercially used reaction to produce polyols such as pentaerythritol and trimethylolpropane.

Tollens condensation Definition: This reaction involves the condensation of formaldehyde with an aliphatic aldehyde having an  -hydrogen, followed by a crossed Cannizzaro reaction to produce geminal bishydroxymethyl derivatives. 定义： 含有-氢的醛(或酮)在碱性催化剂 [如Ca(OH)2, K2CO3, NaHCO3 等] 的存在下，用不含α-氢的甲醛处理，在醛、酮的-碳原子上引入羟甲基的反应称为多伦缩合反应，实际上由醇醛缩合和交叉康尼杂罗反应结合而成。 原料：甲醛和醛 (或酮) 产物：多元醇 (Polyols) 创始人：德国化学家多伦斯 (1891) (July 30, 1841 – January 31, 1918)

Cannizzaro Reacton The Cannizzaro reaction is a chemical reaction that involves the base-induced disproportionation of an aldehyde lacking a hydrogen atom in the alpha position. Cannizzaro first accomplished this transformation in 1853, when he obtained benzyl alcohol and benzoic acid from the treatment of benzaldehyde with potash (potassium carbonate). 康尼杂罗反应的底物结构特点：α-位上无活泼氢的醛； 康尼杂罗反应的反应发生条件：浓 NaOH或KOH(或醇)； 康尼杂罗反应的产物结构特征：醇和酸。

Application Examples Usage: It is commercially used to produce polyols such as pentaerythritol and trimethylolpropane.

苯甲醛与含α-H醛酮的克莱森-施密特反应 b. Claisen-Schimidt Reaction 苯甲醛与含α-H醛酮的克莱森-施密特反应 Reaction Materials: Benzaldehyde and aldehydes (or ketones) withα-H 芳醛和脂肪族醛、酮在碱催化下缩合而成,-不饱和醛、酮的反应称为Claisen-Schimidt反应。 Product 1,3-diphenyl-2-propen-1-one is also called as benzalacetophenone

Synthesis of benzalacetophenone Mechanism ： An enolate anion is an anion derived by loss of a proton from the alpha carbon of a carbonyl group; it is the anion of an enol.

Reaction Mechanism Analysis

Examples：Aromatic

Examples: Heterocycle

Examples：aliphatics 60%

活性比较：酮 < 醛 71% 62%

Review 2012,4,24 Condensation reaction is a chemical reaction in which two molecules or moieties (functional groups) combine to form one single molecule, together with the loss of a small molecule or not losing anything, such as D-A. When two separate molecules react, the condensation is termed intermolecular. If the union is between atoms or groups of the same molecule, the reaction is termed intramolecular condensation, and in many cases leads to ring formation. The word "condensation" suggests a process in which two or more things are brought "together" (Latin "con") to form something "dense", like in condensation from gaseous to liquid state of matter; this does not imply, however, that condensation reaction products have greater density than reactants.

Functionalized alkylation -hydroxyalkylation Aldol condensation, Prins, Benzoin, etc. -chloroalkylation Blanc reaction, -aminoalkylation Mannich, Pictet-Spengler, Strecker,etc.

Review 2012,4,24 Example of intramolecular condensation 1) Dieckmann condensation: two ester groups of a single diester molecule react with each other to lose a small alcohol molecule and form a β-ketoester product. 2) Robinson Annulations The word "condensation" suggests a process in which two or more things are brought "together" (Latin "con") to form something "dense", like in condensation from gaseous to liquid state of matter; this does not imply, however, that condensation reaction products have greater density than reactants.

1.1.1.3 Intramolecular aldol condensation between different groups in a same molecule Robinson Annulations

Robinson Annulations Definition: The Robinson annulation is an organic reaction used to create a six-member ringα,β-unsaturated cyclic ketone, using a ketone (or aldehyde) and methyl vinyl ketone. In addition to methyl vinyl ketone, 1-chloro-3-butanone and isoxazoles will give the same product. Methyl vinyl ketone (or variants thereof) Oxford，UK

Mechanism Analysis Methyl vinyl ketone are essential for the annulation as they are simultaneously a Michael acceptor and able to take part in an aldol condensation. 1. The first step: Michael addition; 2. Second step: Aldol reaction: as the annelation step; 3. Third step: Elimination: via aldol condensation to make the cyclohexenone ring.

1.1.1.4 Directed aldol condensation 含不同α-H 醛酮之间的缩合反应，情况复杂，需要定向醇醛缩合反应。 a） 烯醇盐法：与强碱LDA作用定向生成动力学盐； b） 烯醇硅醚化：单一组分成硅醚化； c） 烯胺法：定向活化α-H生成参与反应。

a）烯醇盐法(低温强碱条件) 与LDA作用定向生成动力学盐 Special example and explanation：

Special Example 具体操作步骤：醛或酮与具位阻的碱如LDA作用，形成烯醇盐再与另一分子醛或酮作用。

b）烯醇硅醚化 具体操作步骤：醛、酮转变成烯醇硅醚，在TiCl4催化下与另一分子醛、酮分子作用。

c）烯胺法： 想让哪种醛的α-H活化，就先让它与环己胺反应。 具体操作步骤： 醛、酮与胺形成亚胺，与LDA形成亚胺锂盐， 再与另一分子醛、酮作用。

普林斯反应 (Prins) (1,3-丙二醇缩醛) 1.1.2 不饱和烃α-羟烷基化 普林斯反应 (Prins) (1,3-丙二醇缩醛)

Prins 甲醛-烯加成反应 Definition：The Prins Reaction is the acid-catalyzed of addition aldehydes to alkenes, and gives different products depending on the reaction conditions. 定义：在无机酸催化剂存在的条件下，甲醛和烯烃加成得到1,3-二醇，进一步和甲醛反应生成环状缩醛的反应称为Prins 甲醛-烯加成反应。 cyclic acetal

Prins Reaction It can be thought of conceptually as the addition of the elements of the gem-diol carbonyl hydrate of the aldehyde across the double bond. 环状缩醛

Prins 甲醛-烯加成反应 Explanations of mechanism: cyclic acetal

Further reaction of cyclic acetal Product cyclic acetal was used as the material of many other reactions, such as: (85%)

Prins 反应注意事项：副反应 如果用HCl作催化剂则生成 注意事项：氯代副产物的生成而不再生成环状缩醛！

1.1.3 Benzoin condensation 芳醛的α-羟烷基化 (安息香缩合) Definition： The benzoin condensation is a reaction between two aromatic aldehydes, particularly benzaldehyde. The reaction is catalyzed by a nucleophile such as the cyanide anion or an N-heterocyclic carbene. The reaction product is an aromatic acyloin with benzoin as the parent compound. 定义：芳香醛在含水乙醇中，以氰化钠(钾)为催化剂，加热后发生双分子缩合生成α-羟基酮的反应。催化剂：NaCN,VB1 An early version of the reaction was developed in 1832 by Justus von Liebig and Friederich Woehler during their research on bitter almond oil. The catalytic version of the reaction was developed by Nikolay Zinin in the late 1830s, and the reaction mechanism for this organic reaction was proposed in 1903 by A. J. Lapworth. Acyloin: 偶姻， 酮醇，酰基醇

Examples

Mechanism 关键：如何制造一个碳负离子？ Benzoyl anion equivalent

Benzoyl anion equivalent 当 R 为吸电子基团时有利于反应但不能生成对称的α-羟基酮，能与苯甲醛反应生成不对称的 α-羟基酮，如： 不对称的α-羟基酮

Other Examples (80%)

1.1.4 Reformatsky Reaction (雷福马斯基反应) Definition: It is an organic reaction which condenses aldehydes (or ketones) with α-halo esters, using a metallic zinc to form β-hydroxy-esters. 定义：醛或酮与α-卤代酸酯和金属锌粉在惰性溶剂中反应,经水解后得到b-羟基酸酯，或脱水得,-不饱和酸酯的反应。

Reformatsky Reaction General Scheme 脱水

Mechanism Analysis Organozinc compounds are prepared from α-halogenesters in the same manner as Grignard Reagents. This reaction is possible due to the stability of esters against organozincs. Due to the very low basicity of zinc enolates, there is hardly any competition from proton transfer, and the scope of carbonyl addition partners is quite broad. In presence of ketones or aldehydes, the organozinc compounds react as the nucleophilic partner in an addition to give β-hydroxy esters. Intermediate：An ester-stabilized organozinc reagent:

Analysis of dehydrate product 脱水产物分析

Influential Effects 1）反应底物结构：-卤代酸酯的活性顺序为： ICH2COOC2H5 > BrCH2COOC2H5 > ClCH2COOC2H5 (95%)

2）用于极性翻转的金属Zn，可用Mg，Li，Al等替代： (81%) (91%)

Examples

Examples Application in Drug Synthesis: Synthesis of Vitamin A（Text book, Example）

Summary of Application of Reformatsky Reaction 1. Synthesis of -hydroxyl carboxylate 2. Synthesis of -hydroxyl carboxylic acid 3. Synthesis of α,-unsaturated carboxylate 4. Synthesis of α,-unsaturated carboxylic acid 5. One of the elongation method of carbon chain of carbonyl compounds.

1.1.5 Grignard and Normant reaction The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides (Grignard reagents) act as nucleophiles and attack electrophilic carbon atoms that are present within polar bonds (e.g. carbonyl group) to yield a carbon-carbon bond, thus altering hybridization about the reaction center. The Grignard reaction is an important tool in the formation of carbon-carbon bonds and for the formation of carbon-phosphorus, carbon-tin, carbon-silicon, carbon-boron and other carbon-heteroatom bonds.

Grignard reagent and reaction Improvement of Grignard reagent: Normant reagent (THF)： 烯烃GR Unpolung 极性反转

1.1.5 Grignard and Normant reaction Grignard reagent and Normant reagent 与羰基化合物(醛、酮)反应，生成相应醇。 Grignard reagent Normant reagent

1.2 α-卤烷基化反应 （Blanc Reaction） Definition：The Blanc chloromethylation is the chemical reaction of aromatic rings with formaldehyde and hydrogen chloride catalyzed by zinc chloride to form chloromethyl arenes. 定义： 芳香化合物用甲醛、氯化氢及ZnCl2或AlCl3或质子酸处理时，在环上引入氯甲基的反应称为Blanc 氯甲基化反应。 通式 机理: (苯环上有供电子基有利于反应,因为此为亲电反应)

Usage and significance 氯甲基化产物 ArCH2Cl 可转化为： ArCH2OH, ArCH2OR, ArCHO, ArCH2CN, ArCH2NH2(R2)，及延长碳链。

Elongation of carbon chain： Blanc 氯甲基化反应可用于延长碳链：

Examples

1.3 α-aminoalkylation α-氨烷基化反应 Mannich Reaction –3CR 2. Pictet-Spengler Reaction (Intramolecualar special MR two molecules: one with two functional groups (amine and active C-H) and one is aldehyde) 3. Strecker Reaction

1. Mannich Reaction Definition：This multi-component condensation of a nonenolizable aldehyde, a primary or secondary amine and an enolizable carbonyl compound affords aminomethylated products. The iminium derivative of the aldehyde is the acceptor in the reaction. 定义：含有α -活泼氢的醛、酮类化合物与甲醛及胺(伯胺、仲胺或氨)反应，一个α-活泼氢被胺甲基取代，所得产物-氨基酮类化合物称为曼尼奇碱，该反应称为曼尼奇氨甲基化反应，又称为胺甲基化反应。

Structure features of 3 reactants 含活泼氢的化合物：酮、醛、酸、酯、腈、硝基烷、炔、酚及杂环化合物； 醛：甲醛、三聚甲醛、多聚甲醛及活性大的脂肪醛和芳香醛； 胺：仲胺、伯胺及氨。 Amine：Primary amine，sencondary amine，anime

Mechanism 亲电取代反应 iminium The involvement of the Mannich Reaction has been proposed in many biosynthetic pathways, especially for alkaloids.

Influential effects 胺: 仲胺氮上只有一个氢，反应产物单一，而氨或伯胺，产物复杂，伯胺发生两次反应; 含有两种α-H的不对称酮反应发生在多取代α-碳上; α,β-不饱和酮的反应发生在饱和的α-碳上; 酚类和活化芳杂环，氨甲基进入电荷密度较高的位置。

Examples

Examples 抗疟疾药常洛林

改性聚丙烯酰胺阳离子絮凝剂 聚丙烯酰胺阳离子絮凝剂对废水中各种微粒产生吸附桥架作用，中和表面带有负电荷的废水微粒 ，使微粒脱稳、絮凝有助于沉降和过滤脱水。 发生Mannich反应使烷链增加，增加其疏水性，使絮凝速度加快，絮体增大，改善效果。

Other examples C-氨甲基化产物 芦竹碱的合成 Scopolamine Gramine

Transformation of functional group 由芦竹碱转化为吲哚乙酸 制备多一个碳的同系物

Special case of Mannich reaction Pictet-Spengler： P-S is a chemical reaction in which a β-arylethylamine such as tryptamine undergoes ringclosure after condensation with an aldehyde or ketone. Usually an acidic catalyst is employed and the reaction mixture heated, but some reactive compounds give good yields even at physiologic conditions. 四氢异喹啉类合成反应： -芳基乙胺和羰基化合物在酸性溶液中缩合生成1,2,3,4-四氢异喹啉的反应称为Pictet-Spengler反应。 Pictet-Spengler Reaction (Intramolecualar special MR two molecules: one with two functional groups (amine and active C-H) and one is aldehyde)

Mannich氨甲基化反应的特例 药物合成方面的应用： 四氢异喹啉类化合物具有广泛的生物活性。 Example:

Strecker amino acid synthesis Definition: The Strecker amino acid synthesis is a series of chemical reactions that synthesize an amino acid from an aldehyde (or ketone). The aldehyde is condensed with ammonium chloride in the presence of potassium cyanide to form an α-aminonitrile, which is subsequently hydrolyzed to give the desired amino-acid. 定义：醛或酮用氰化钠及氯化铵处理可一步得到-氨基腈，水解生成-氨基酸的反应称为Strecker氨基酸合成反应，是制备-氨基酸的方便方法！ 通式：

Mechanism Analysis

Examples 制备α-氨基酸

Section II  -Functionalized alkylation

2.1β-hydroxylalkylation 2.1.1 2.1β-hydroxyl alkylation on aromatic hydrocarbon 定义：在路易斯酸催化下，芳烃与环氧乙烷发生付克反应，生成-芳基乙醇的反应。 通式： Friedel-Crafts Reaction Catalyst：Lewis acid： AlCl3, SnCl4, etc.

β-hydroxylalkylation on Aromatic hydrocarbons Example： Electron donor 电子给体 Carbanion acceptor 碳负离子接受体

2.1.2 β-hydroxylalkylation on active methylene compounds 含有活性亚甲基的化合物与环氧乙烷在碱催化下发生的羟乙基化反应。 例： (70%)

2.1.3 β-hydroxylalkylation on Organic metallic compounds (62%) (89%) Metal: Li, Mg, Cu, etc.

2.2 β–Carbonylalkylation β–羰烷基化反应 2.2.1 Michael addition(迈克尔加成) Definition: The Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an , -unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds. Many asymmetric variants exist. 定义：有活泼的亚甲基化合物在碱催化作用下，形成的碳负离子，和,-不饱和羰基化合物的活泼碳-碳双键的亲核加成反应，是活泼亚甲基烷基化的一种重要方法，称为迈克尔亲核亚甲基加成反应，简称迈克尔加成，也称1,4-共轭加成。 意义：麦克尔加成最有价值的有机合成反应之一，是构筑碳-碳键的最常用方法之一。

General Scheme 碳负离子接受体 Cat. 电子给体 A，A’’，A’’ 分别为：-CHO, -COR, -COOR, -CONH2 , -CN, -NO2 , -SOR, SO2R 等吸电子基团。

Reaction Mechanism carbanion Nucleophilic addition

Typical Scheme of Michael Addition Cat.: Base Carbanion acceptor 碳负离子接受体 Electron donor 电子给体

Michael 反应底物结构的影响 电子给体：活泼亚甲基化合物、烯胺、氰乙酸酯类、酮酸酯、硝基烷类、砜类等； 碳负离子接受体：-不饱和醛、酮、酯，不饱和腈、不饱和硝基化合物以及易于消除的曼尼希碱；

Michael 反应催化剂的种类的影响 催化剂： 碱性：醇钠(钾)、氢氧化钠(钾)、金属钠砂、氨基钠、氢化钠、哌啶、吡啶、三乙胺、季铵碱； 催化剂量：T：0.1-0.3当量， M：等量收率可提高，选择性可增强。 酸性： 三氟甲磺酸、Lewis酸、氧化铝、 无机盐：氯化铁、氟化钾

Micheal addition on Asymetrical ketone Controling methods：Examples

Application of Michael Addition Structure modification of natural product. 天然产物的结构改造； Introduction of 3 carbon-chain. 引进三个碳原子的侧链； Introduction of polycarbon-chain. 引入多个碳原子的侧链； Synthesis of bicyclic or polycylic unsaturated fused- ring ketone. 合成二环或多环不饱和稠和酮类。

Structure modification of natural product. Application of Michael reaction Structure modification of natural product.

Examples of Michael reaction Introduction of 3 carbon-chain. 100% 53%

Examples of Michael reaction Introduction of polycarbon-chain. 通过季铵碱分子内消除反应

Application of Michael Reaction Synthesis of bicyclic or polycylic unsaturated fused- ring ketone. 首先形成甲基乙烯基酮 Methyl vinyl ketone 1,5-Diketone 合成二环或多环不饱和稠和酮类

Robinson Annulation Michael Reaction 重要应用: Robinson Annulation

Robinson Annulations Definition: The Robinson annulation is an organic reaction used to create a six-member ringα,β-unsaturated cyclic ketone, using a ketone (or aldehyde) and methyl vinyl ketone. In addition to methyl vinyl ketone, 1-chloro-3-butanone and isoxazoles will give the same product. Methyl vinyl ketone (or variants thereof) Sir Robert Robinson Oxford，UK

Mechanism Analysis Methyl vinyl ketone are essential for the annulation as they are simultaneously a Michael acceptor and able to take part in an aldol condensation. 1. The first step: Michael addition; 2. Second step: Aldol reaction: as the annelation step; 3. Third step: Elimination: via aldol condensation to make the cyclohexenone ring.

Synthesis of bicyclic compound or polycyclic unsaturated ketone Robinson Annulation 63~65%

Section III Methylenation reaction 3.1 Wittig Reaction (羰基烯化反应) 定义：醛或酮与烃代亚甲基三苯膦发生亲核加成反应，醛、酮分子中羰基的氧原子被烃代亚甲基所取代，生成相应的烯类化合物及氧化三苯膦的反应称Wittig羰基成烯反应。 Georg Wittig (June 16, 1897 – August 26, 1987) was a German chemist who reported a method for synthesis of alkenes from aldehydes and ketones using compounds called phosphonium ylides in the Wittig reaction. He shared the Nobel Prize in Chemistry with Herbert C. Brown in 1979. Georg Wittig (June 16, 1897 – August 26, 1987) was a German chemist who reported a method for synthesis of alkenes from aldehydes and ketones using compounds called phosphonium ylides in the Wittig reaction. He shared the Nobel Prize in Chemistry with Herbert C. Brown in 1979. Definition: The Wittig Reaction is a chemical reaction of an aldehyde or ketone with a triphenyl phosphonium ylide (often called a Wittig reagent) to give an alkene and triphenylphosphine oxide.

3.1 Witting Reaction Wittig reagent： 硫和磷与碳结合时，碳带负电荷，硫或磷带正电荷彼此相邻，这种结构的化合物称为Ylide(叶立德)。由磷形成的Ylide称为磷Ylide，又称为Wittig试剂，其结构可表示如下： Georg WittigBornJune 16, 1897) Berlin, GermanyDiedAugust 26, 1987) (aged 90)NationalityGermanyFieldsChemistryInstitutionsUniversity of Marburg TU Braunschweig University of Freiburg University of TübingenAlma materUniversity of MarburgDoctoral advisorKarl von AuwersDoctoral studentsWerner TochtermannKnown forWittig reaction 1,2-Wittig rearrangement 2,3-Wittig rearrangement Potassium tetraphenylborateNotable awardsNobel Prize in Chemistry (1979) 烃代亚甲基三苯膦 烃代亚甲基三苯膦 称为Wittig 试剂 Georg Wittig

Preparation of Wittig reagent RX： RBr Solvent：Et2O, benzene,DMF, DMSO Base： NaNH2, RONa, n-BuLi,

General Scheme and structure features of reaction substrate R1,R2,R3,R4：氢、烷基、烯基、芳基、 含有各种官能团的芳基和烷基等。

Mechanism of Wittig reaction

Features of Wittig Reaction 羰基被碳-碳双键代替形成立体专一性的烯类。 和a-不饱和醛或酮反应，一般不发生1,4-加成，可利用此性质来合成共轭多烯化合物，如叶红素、维生素A等的合成。 合成的双键能位于在能量不利的位置。

Wittig Reaction: Elongation of carbon chain

Elongation of carbon chain

3.2 羰基α-位的亚甲基化 3.2.1 Knoevenagel condensation reaction （活性亚甲基化合物的亚甲基化） 定义：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，发生失水缩合得到α,β -不饱和化合物及其类似物，该反应称为脑文格反应。 Definition：A Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule of water is eliminated (hence condensation). The product is often an α,β - conjugated enone. It is a modification of the Aldol condensation.

3.2.1 Knoevenagel condensation General Scheme Emil Knoevenagel Basic Catalysts 氨、胺、吡啶、哌啶、二乙胺、氢氧化钠等

Emil Knoevenagel

Influential effects 1. 底物醛酮的位阻影响： 醛比酮好，位阻小的酮比位阻大的酮好

2.活性亚甲基化合物的结构影响 ① 酸性很强-活泼 Eg：

2.活性亚甲基化合物的结构影响 ② 活性稍弱于 ① Eg：

2.活性亚甲基化合物的结构影响 ③ 用醇钠强碱作催化剂 Eg：

Application of Knoevenagel condensation 丙二酸与醛的缩合物受热即自行脱羧，是合成α,β-不饱和酸的较好方法之一。 Eg 1： 呋喃丙烯酸的制备（药合实验-4） Eg 2: Eg 3: 吡格列酮、罗格列酮和苏尼替尼的合成。

Section IV Darzens Reaction α,β-环氧烷基化 Darzens reaction (also known as Darzens condensation or glycidic ester condensation) is the chemical reaction of a ketone or aldehyde with an α-haloester to form an α,β-epoxy ester, also called a “glycidic ester” which was discovered by the organic chemist Auguste George Darzens in 1904. 定义：醛、酮在强碱作用下与α-卤代羧酸酯缩合，生成α,β-环氧羧酸酯（缩水甘油酯）。 通式 R1，R2最好有一个是芳基或是 glycidic ester

Further reaction of glycidyl ester 缩水甘油酯 可制备比原来缩水甘油酯的羧酸少一个碳原子的醛酮

Mechanism of Darzens Reaction

Scopes of Darzens Reaction 脂肪族，脂环族，芳香族杂环以及α,β-不饱和醛或酮，但脂肪醛的反应产率低。 α-卤代羧酸酯可由其他含有α-活泼氢的化合物替代，如α-卤代醛，α-卤代酮，α-卤代酰胺等和醛类或酮类化合物也能发生类似反应。 Eg： α-卤代酮

Examples of Darzens reaction in Medicinal synthesis

Section V Cycloaddition 环加成反应 Diels-Alder Reaction （双烯合成） 定义：含有一个活泼的双键或叁键的烯或炔类和二烯或多烯共轭体系发生1,4-加成，形成六员环状化合物的反应称为Diels-Alder反应。 The Diels–Alder reaction is an organic chemical reaction (specifically, a cycloaddition) between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly-formed ring are not carbon. 应用： 该反应易进行且反应速度快，应用范围广，是合成环状化合物的非常重要方法。 Some of the Diels–Alder reactions are reversible; the decomposition reaction of the cyclic system is then called the retro-Diels–Alder.

Diels-Alder Reaction Diels-Alder Reaction (双烯合成反应)

D-A Cycloaddition 反应物活性：电子从丁二烯流向乙烯，因此带有吸电子基团的亲双烯体的活性高。 如：

Summary of Diels-Alder reaction R1为吸电子基 (Electron withdrawing groups) 如-CHO, -COR, -COOR, -CN 等，则有利于环合； R 为供电子基 (Electron donating groups)有利。

Examples Rules of DA cyclo-addition 优先生成内向加成 1）顺式加成 2）内向加成 b) 2-取代-1,3-丁二烯： 1,4-加成产物

补充：其他重要人名反应 Horner Reaction Stobbe Reaction Perkin Reaction Erlenmeyer-Plöchl Reaction

Horner Reaction 定义：霍纳尔-沃兹沃思-埃蒙斯反应，常称为维蒂希-霍纳尔反应 (Wittig-Horner Reaction) 是 Wittig 反应的改进，用稳定的膦酸酯碳负离子，代替磷叶立德，与醛、酮反应生成烯烃，产物主要为E-型烯烃。 Definition：The Horner-Wadsworth-Emmons reaction (or HWE reaction) is the chemical reaction of stabilized phosphonate carbanions with aldehydes (or ketones) to produce predominantly E-alkenes.

Stobbe Reaction 丁二酸双酯与羰基化合物在碱(乙醇钠、叔丁醇钾)存在下缩合得α-亚甲基丁二酸单酯的反应，称为斯陶伯缩合。产物二元羧酸单酯，经水解可得不饱和二元酸。 The Stobbe condensation is a modification specific for the diethyl ester of succinic acid requiring less strong bases. An example is its reaction with benzophenone:

Stobbe Condensation Example

Stobbe Reaction -2 某些β-酮酸酯和醚的类似物也可与醛或酮反应，得到斯陶伯缩合产物。

Perkin Reaction Definition：Organic reaction that can be used to make cinnamic acids by the aldol condensation of aromatic aldehydes and acid anhydrides in the presence of an alkali salt of the acid. 定义：芳香醛与酸酐在碱性催化剂存在下，发生类似羟醛缩合反应得到 β-芳基-α,β-不饱和羧酸。通常使用与酸酐对应的羧酸盐作催化剂。 It was developed by William Henry Perkin

Erlenmeyer-Plöchl Reaction Definition： Erlenmeyer-Plöchl azlactone and amino acid synthesis is a series of chemical reactions which transform glycine to various other amino acids via an oxazolone and an azlactone, which include the following 3 steps: 1. 甘氨酸的苯甲酰衍生物(马尿酸)在乙酸酐存在下发生分子内环合，生成中间体2-苯基噁唑酮。 2. 2-苯基噁唑酮有两个酸性氢，在乙酸钠和乙酸酐存在下与苯甲醛缩合为吖内酯，即亚苄基苯基噁唑酮。 3. 吖内酯再经还原，得到苯丙氨酸。 Result：Transformation for glycine to other amino acid via the intermediate of oxazolone and an azlactone.

Erlenmeyer-Plöchl Reaction 2-苯基噁唑酮 Hippuric acid 马尿酸 苯甲酰甘氨酸 吖内酯: 亚苄基苯基噁唑酮

Review of this chapter Condensation reaction (C-C键形成): -羟烷基、卤烷基、氨烷基化反应 -羟烷基、 -羰烷基化反应 亚甲基化反应 ,-环氧烷基化反应 环加成反应

Review Question? How to get β-hydroxyl substituted carbonyl compounds by avoiding the formation of α,β- unsaturated alkene as much as possible? Answer: By controlling the temperature.

Review：定向醇醛(酮)缩合 1. 醛或酮与具位阻的碱如LDA(二异丙胺锂)作用，形成烯醇盐再与另一分子醛或酮作用， 2. 醛、酮转变成烯醇硅醚，在TiCl4催化下与另一分子醛、酮分子作用， 3. 醛、酮与胺形成亚胺，与LDA形成亚胺锂盐，再与另一分子醛、酮作用。

Review：Mannich 反应的用途 1. 聚丙烯酰胺阳离子絮凝剂的工业改性 2. 制备C-氨甲基化产物 1. 聚丙烯酰胺阳离子絮凝剂的工业改性 2. 制备C-氨甲基化产物 3. Michael 加成的反应物 4. 官能团的转化(如亲核试剂置换) 5. 制备多一个碳的同系物

Summary of Application of Reformatsky Reaction 1. 合成-羟基羧酸酯 2. 合成-羟基羧酸 3. 合成α,-不饱和羧酸酯 4. 合成α,-不饱和羧酸 5. 醛、酮增长碳链的方法之一

04,26,2012Review: Formation of C=C: olefination 1. Robinson annulation 2. Refomasky reaction 3. Wittig reaction 4. Knoevenagel condensation 5. Organozinc reagents with aldehydes 6. Olefin metathesis Carbon–Carbon Double-Bond Formation from the Reaction of Organozinc Reagents with Aldehydes Catalyzed by a Nickel(II) Complex. — The approach offers a new and efficient method for the selective formation of (E)-alkenes. A number of functional groups are tolerated under these mild conditions. — (WANG, JIN-XIAN; FU, YING; HU, YULAI; Angew. Chem., Int. Ed. 41 (2002) 15, 2757-2760;