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单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,5,甲醛与含有,a,-,活泼氢的醛、酮之间的缩合,三羟甲基丙烷,6,(a),烯醇盐法,7,(b),烯醇硅醚法,8,(c),亚胺法,9,（,2,）,芳醛与,a,-,活性氢的醛、酮的缩合,10,碱催化下，,1,位比,3,位较易形成碳负离子；,而在酸性催化下，取代基多的烯醇式比较稳定。,11,应用特点,制备反式芳丙醛（,Claisen-Schmidt,）,12,13,制备手性,b-,羟基醛,14,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, 2395,制备手性,b-,羟基醛,15,（,3,）分子内的羟醛缩合,16,Robinson,环化,17,18,19,20,21,2.,不饱和烃的,a-,羟烷基化（,Prins,反应,）,22,23,Mechanism,24,25,26,3.,安息香缩合（,Benoin,缩合）,27,28,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,29, 催化剂的影响,NaCN,剧毒，可用噻唑鎓盐、咪唑鎓盐等代替,30,31,32,Example,33,34,4.,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：,35,36,metal: Zn, Mg, Cd, Ba, In, Ge, Co, Ni, Ce; metal salt: SmI2, CrCl2, TiCl2, CeX3, Na2Te, R3SnLi,R3Sb/I2, Et2AlCl,37,most often ether solvents are used such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane and dimethoxyethane (DME), but mixtures of these solvents with aromatic hydrocarbons and more polar solvents such as acetonitrile, dimethyl formamide (DMF), dimethyl sulphoxide (DMSO), and hexamethylphosphoric triamide (HMPTA) are also used.,38,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。,39,40,例如,:,加入,(CH,3,O),3,B/THF,可提高收率,41,42,43,（,2,）,Grignard,反应,44,45,46,机理,:,47,48,影响因素,1) the reagents are predominantly prepared by reacting alkyl, aryl, or vinyl halides with magnesium 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);,49,50,51,二、,a,-,卤烷基化反应,(Blanc,反应,),氯甲基化反应为亲电取代反应,52,影响因素,也可用,ZnCl,2,(,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%),53,54,引入,-CH,2,Cl,后，可进一步转化成其他官能团并增长碳链。,55,56,三、,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,),1. Mannich,reaction,57,反应机理,58,59,碱催化反应,60,如：,(90%),抗胆碱药阿托品的中间体,61,62,63,64,Introduction,65,1. Metal Catalysis,2. Proline Catalysis,3. Brnsted Acid-Catalysis,4. Protonated Chiral Catalysis,5. ACDC,6. H-Bond Catalysis,7. PTC,66,Trost, B. M.,J. Am. Chem. Soc.,2019,128, 2778-2779.,67,Proline catalysis,68,69,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,70,Protonated Chiral Catalysis,J. Am. Chem. Soc.,2019,126, 3418-3419,71,Ishihara, K.,J. Am. Chem. Soc,2019,130, 1685816860.,72,H-Bond Catalysis,73,Jacobsen, E. N.,Angew. Chem. Int. Ed.,2019,44, 466468.,74,2.,Pictet-Spengler reaction,75,76,反应机理可能如下：,芳乙胺与醛首先作用得,-,羟基胺,，再脱水生成,亚胺,，然后,在酸催化,下发生,分子内亲电取代反应而闭环,，所得四氢异喹啉以,钯碳脱氢,而得异喹啉。,77,78,Baldwin,环化规则,79,Baldwin,环化规则,SP,3,= tet,；,SP,2,= trig,；,SP = dig,SP,3,: 5-6- endo,禁阻,SP,2,: 3-5-endo,禁阻,SP: 3-4- exo,禁阻,其他允许,80,3. Strecker,反应,（,1,）反应通式,81,（,2,）反应机理,82,醛或酮,与,氰化氢和过量氨,（,可用氰化钠及氯化铵水溶液代,）作用得到,-,氨基腈,，经酸或碱水解生成,-,氨基酸,的反应称为,Strecker,氨基酸合成反应。该反应是制备,-,氨基酸的方便方法,。,83,84,85,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,86,2.,反应机理,87,苯环连在取代基多的,C,上,3.,应用特点,（,1,）区域选择性,88,（,2,）立体选择性,构型反转,89,（,3,）制备环内酯,90,二、,b,-,羰烷基化反应,Michael,加成反应,91,92,100%,53%,93,Robinson,增环反应,6365%,94,95,96,Micheal,反应的应用,97,98,第四节 亚甲基化反应,一 羰基烯化反应,（,1,）反应通式及机理,99,（,2,）影响因素,100,the ylides are water as well as oxygen-sensitive,；,the phosphorous ylides chemoselectively,react with aldehydes (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,；,101,102,103,此外，,Wittig,试剂尚可与烯酮、异腈酸酯、酸酐、亚胺、亚硝基物反应，生成,Wittig,产物，例如：,104,Wittig,试剂亦可与二氧化碳反应，产物经水解得羧酸或羟热解脱羧成丙二烯衍生物。,105,The,Wittig reaction has several important variants:,HWE Reaction,106,Wittig,试剂改良,107,Wittig -Horner,反应：主要是,E-,式烯烃产物,108,利用膦酸酯反应进行,Wittig,反应，其产物烯烃主要是,E-,式异构体。但金属离子、溶剂、反应温度及膦酸酯中醇的结构均可影响其立体选择性，如膦酸酯（,55,）与苯甲醛在溴化锂存在下可得单一,E-,式异构体（,56,）。而膦酸酯,(57),与醛,(58),在低温下反应，产物主要是,Z-,式异构体（,59,）。,109,110,111,112,二 羰基,a,位的亚甲基化反应,Knoevenagel,反应,113,碱性催化剂是：氨、胺、吡啶、哌啶、二乙胺、及其盐类、氢氧化钠等,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,),或其羧酸盐的存在下发生醇醛型缩合，再脱水得到,a,b-,不饱和化合物。,114,（,2,）反应机理,115,116,位阻影响：醛比酮好，位阻小的酮比位阻大的酮好,117,118,119,120,121,2.,Stobbe,反应,（,1,）反应通式,122,（,2,）反应机理,123,124,（,3,）应用,制备烯酸,125,126,127,128,3.,Perkin,反应,(1),反应通式,129,（,2,）反应机理,130,131,（,3,）影响因素,芳香醛结构影响,吸电子活性增强，给电子相反,132,碘番酸中间体,133,催化剂的影响,相应羧酸的钾盐、钠盐；铯盐效果更好,134,（,4,）应用,135,136,137,138,第五节,a,、,b,-,环氧烷基化反应,(Darzens,反应,),1.,反应通式,EWG = CO,2,R, CN, SO,2,R, CONR,2, C(=O), C(=NR);,Y = O, NR;,139,2.,反应机理,140,3.,影响因素,Aliphatic aldehydes usually give lower yields,；,-,Chloro esters are preferable to bromo or iodo esters, since they give higher yields,；,-,halo sulfones,nitriles,ketones, ketimines, thiol esters,or amides,can also be used to obtain the corresponding derivatives,；,141,4.,应用特点,142,醛、酮同系化,C+1,143,144,布洛芬的合成,145,不对称,Darzens,反应,146,第六节 环加成反应,EDG (electron-donating group),= alkyl,O-alkyl, N-alkyl, etc.,EWG (electron-withdrawing,group) = CN, NO2, CHO, COR,COAr, CO2H, CO2R, COCl etc.,一、,D-A,反应,147,Mechanism,148,影响因素及应用特点,共轭二烯双键必需是顺型的,顺式原理,149, 内向加成原理,150,加成定位规则,151,Example,152,153,154,155,156,157,二、,1,3,偶极环加成,Huisgen Cycloaddition/1,3-Dipolar Cycloaddition,158,1,3-Dipolar compounds contain one or more heteroatoms and can be described as having at least one mesomeric structure that represents a charged dipole.,159,Mechanism of the Huisgen 1,3-Dipolar,Cycloaddition,1,3-,偶极环加成与,Diels-Alder,反应机理类似，为协同反应。,160,1. Azomethine Ylides,2. Azomethine Imines,161,3. Nitrones,162,4. Azides,163,5. O3 / Carbonyl Oxides,164,常用,1,3-,偶极体系的制备,165,影响偶极反应的主要因素,吸电子基团和给电子基团取代基均使偶极反应活性增强，而且共轭效应大于诱导效应；,反式烯烃活性大于顺式烯烃，如反式丁烯二酸二甲酯的活性是顺式的,74,倍；,环大小对活性影响也比较大，环戊烯是环己烯的,9,倍。,常见的,1,3-,偶极体系见,药物合成反应,p161,表,4-3,166,167,168,三、碳烯、氮烯对不饱和键的加成,Carbene-,电中性二价碳中间体，两电子自选方向相同为三线态，相反为单线态,169,单线态与烯烃的反应有立体定向性,三线态与烯烃的反应不具有立体定向性,单线态,三线态,170,here,171,Simmons-Smith cyclopropanation,.,172,单线态碳烯通常通过可以有重氮甲烷的光分解或热分解制得；而三线态碳烯可以通过重氮甲烷在光敏剂二苯酮存在下光照分解。,173,174,175,176,177,Example,178,179,再见,
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