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1、Chapter 4,Condenation Reaction,第四章 缩合反应,第一节 a-羟烷基、卤烷基、氨烷基化反应,一、a-羟烷基化反应 1.醇醛缩合反应(Aldol缩合) (1)含有a-活泼氢的醛或酮的自身缩合,碱催化机理:,甲醛与含有a-活泼氢的醛、酮之间的缩合,三羟甲基丙烷,催化剂的影响 以碱催化剂为主，酸催化剂应用较少 应用特点 定向醇、醛缩合 (a) 烯醇盐法,(b) 烯醇硅醚法,（2）芳醛与a-活性氢的醛、酮的缩合,应用特点 制备反式芳丙醛,有机小分子脯氨酸催化 直接 Aldol 反应,List, B. et al, J. Am. Chem. Soc. 2000, 122,
2、2395,制备手性b-羟基醛,（3）分子内的羟醛缩合,Robinson环化,2. 不饱和烃的a羟烷基化（Prins反应）,Mechanism,3. 安息香缩合,影响因素 芳醛结构的影响 强吸电子、强供电子对反应都不利； 自身缩合、交叉缩合, 催化剂的影响 NaCN剧毒，可用噻唑鎓盐、咪唑鎓盐等代替,Example,4.有机金属化合物的a-羟烷基化,(1) Reformatsky反应: 醛或酮与a-卤代酸酯在金属锌粉存在下缩合而得b-羟基酸酯或脱水得a、b-不饱和羧酸酯的反应：,metal: Zn, Mg, Cd, Ba, In, Ge, Co, Ni, Ce; metal salt: SmI2
3、, CrCl2, TiCl2, CeX3, Na2Te, R3SnLi, R3Sb/I2, Et2AlCl,most often ether solvents are used such as diethyl ether,tetrahydrofuran, 1,4-dioxane and dimethoxyethane, but mixtures of these solvents with aromatic hydrocarbons and more polar solvents such as acetonitrile, dimethyl formamide, dimethyl sulpho
4、xide, and hexamethylphosphoric triamide are also used;,催化剂,锌粉必须活化，常用20%盐酸处理，再用丙酮、乙醚洗涤，真空干燥。 亦可用K、Na、Li等还原无水氯化锌，此法活性较高。 Mg, Cd, Ba, In, Ge, Co, Ni, Ce等。,例如:,加入(CH3O)3B/THF可提高收率(如上),（2）Grignard反应,机理:,影响因素 1) the reagents are predominantly prepared by reacting alkyl, aryl, or vinyl halides with magnesi
5、um metal in aprotic nucleophilic solvents (e.g., ethers, tertiary amines); 2) the reagents are usually thermodynamically stable but air and moisture sensitive and incompatible with acidic functional groups (e.g., alcohols, thiols, phenols, carboxylic acids, 1, 2 amines, terminal alkynes);,二、 a-卤烷基化反
6、应(Blanc反应),3.影响因素 也可用ZnCl2(干)等Lewis酸。苯环上供电子基,有利于反应进行。吸电子基不利于反应进行。,(87%),引入-CH2Cl后，可进一步转化成其他官能团并增长碳链。,三、a-氨烷基化反应,Mannich反应：有活泼氢的化合物(醛、酮等) 与甲醛、胺进行缩合，H原子被a-氨甲基 取代称为 a-氨甲基化反应(Mannich反应),反应机理,如：,(90%),抗胆碱药阿托品的中间体,Introduction,1. Metal Catalysis 2. Proline Catalysis 3. Brnsted Acid-Catalysis 4. Protonated
7、 Chiral Catalysis 5. ACDC 6. H-Bond Catalysis 7. PTC,Trost, B. M. J. Am. Chem. Soc.2006, 128, 2778-2779.,Proline catalysis,Brnsted acid-catalysis,磷原子的四齿结构 (2) 磷酸的酸性足以诱捕亚胺 (3) 双功能手性催化剂,4. Protonated Chiral Catalysis,J. Am. Chem. Soc. 2004, 126, 3418-3419,Ishihara, K. J. Am. Chem. Soc 2008, 130, 16858
8、16860.,H-Bond Catalysis,Jacobsen, E. N. Angew. Chem. Int. Ed. 2005, 44, 466468.,2. Pictet-Spengler reaction,Baldwin环化规则,Baldwin环化规则 SP3 = tet；SP2 = trig；SP = dig SP3: 5-6- endo 禁阻 SP2: 3-5-endo 禁阻 SP: 3-4- exo 禁阻 其他允许,（3）影响因素 only -arylethylamines with electron-donating substituents afford high yiel
9、ds; the reaction is usually carried out with a slight excess of the carbonyl compound (to ensure the complete consumption of the amine) in either protic or aprotic medium;,3. Strecker反应 （1）反应通式,（2）反应机理,（3）应用-Corey，1999,第三节 b-羟烷基、 b-羰烷基化反应,一 b-羟烷基化反应 1.反应通式-F-C反应,2. 反应机理,苯环连在取代基多的C上,3.应用特点,（1）区域选择性,（
10、2）立体选择性 构型反转,（3）制备环内酯,二、 b-羰烷基化反应,Michael加成反应,反应机理:,（3）影响因素,1) the nucleophile (Michael donor) can be derived by the deprotonation of CH-activated compounds such as aldehydes, ketones, nitriles, -dicarbonyl compounds, etc. as well as by the deprotonation of heteroatoms;,2) depending on the type and
11、strength of the electron-withdrawing group (negative charge stabilizing group), the use of even relatively weak bases is possible (e.g., NEt3);,（4）应用,第四节 亚甲基化反应,一 羰基烯化反应 （1）反应通式及机理,（2）影响因素,the ylides are water as well as oxygen-sensitive； the phosphorous ylides chemoselectively react with aldehydes
12、(fast) and ketones (slow), other carbonyl groups (e.g., esters, amides) remain intact during the reaction; the stereoselectivity, E-or Z-selectivity, is influenced by many factors: type of ylide, type of carbonyl compound, nature of solvent；,The Wittig reaction has several important variants: HWE Re
13、action,the phosphonate carbanions are more nucleophilic than the corresponding phosphorous ylides, so they readily react with practically all aldehydes and ketones under milder reaction conditions； the by-product dialkyl phosphates are water-soluble, so it is much easier to separate them from the al
14、kene products than from the water-insoluble triphenylphosphine oxide., high (E)-selectivity for disubstituted alkenes under much milder conditions than normally used in Wittig reactions； the (E)-selectivity is maximized by increasing the size of the alkyl group of the R1 or R2 substituents, There ar
15、e an important modifications of the HWE olefination: in the Still-Gennari modification R1=OCH2CF3 and the reaction affords (Z)-olefins exclusively； for base-sensitive substrates, the use of a metal salt (LiCl or NaI) and a weak amine base (e.g., DBU) has proven effective to avoid epimerization.,（4）应
16、用,二 羰基a位的亚甲基化反应 活性亚甲基的亚甲基化 Knoevenagel 反应 （1）反应通式,（2）反应机理,（3）影响因素, the nature of the catalyst is important, usually primary, secondary, and tertiary amines and their corresponding ammonium salts, certain Lewis acids combined with a tertiary amine (e.g., TiCl4/Et3N).,the by-product of the reaction is water and its removal from the reaction mixture by means of azeotropic distillation, the addition of molecular sieves, or other dehydrating agents shifts the equilibrium towa
