有机合成课件1

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,*,（三）,.,烯胺的烃化反应,1963,年, G. Stork,使用醛和叔丁基胺形成烯胺,sichiff,碱,p-TsOH,甲苯带水,(Dean and Stark apparatus),或用无水,K,2,CO,3,除水,优点,(1),不需要碱或其他催化剂,减少羰基的自身缩合,(2),可以制备单烷基化产物,(3),对于不对称的酮,取代发生在取代基较少的位置,烯胺的,Michael,反应,:,取代基少的位置,酮的,Michael,反应,:,取代基较多的位置,6-,甲氧基,-1-,甲基,-2-,四氢萘酮的制备：,1.,烯胺的制备,N,2,，,17.6g(0.1mol) 6-,甲氧基,-2-,四氢萘酮,10.6g(0.15mol),四氢吡咯（除水）,300mL,苯,回流分水（约,2mL,）,减压蒸去溶剂，用正己烷重结晶得无色晶体（空气中存放,1-2,天）。,6-,甲氧基,-1-,甲基,-2-,四氢萘酮的制备：,2.,烯胺的反应,N,2,，,18.6g(0.08mol) 2-,四氢吡咯基,-1,3-,二氢,-6-,甲氧基萘,30mL,CH,3,I,75mL 1,，,4-,二噁烷（除水）,回流,18h,加,35mL,水和,1.5mL,乙酸，回流,5h.,减压蒸去溶剂，加,200mL,水，乙醚萃取，干燥，蒸去溶剂，减压蒸出,6-,甲氧基,-1-,甲基,-2-,四氢萘酮,（,113-115,o,C,）。,(81%),在有支链的一侧，烯醇负离子稳定。,酰基化,:,可在碳上酰基化,并用于增长碳链,合成昆虫激素的中间体,-,乙酰基己酸,三、麦克尔,Michael,反应,(,一,),概述,碱性条件,活泼亚甲基化合物与,a, b,-,不饱和羰基化合物发生,1,4-,加成反应,SO,2,Ph，,1.,（,Michael,受体）,a, b,-,不饱和羰基化合物，,a, b,-,不饱和腈等,A,：,CHO,COR,COOR,COAr,，,CONR,2,，,NO,2,，,CN,，,SO,2,Ph,，,SOPh,2.,亲核试剂：活泼甲基和亚甲基化合物,乙酰乙酸乙酯,丙二酸酯,乙酰丙酮,b-,酮酸酯,醛,酮,腈,硝基化合物,3.,碱,:,醇钠、氨、胺,4,溶剂：苯类、醇类、二氧六环,通式：,（二）应用,1,制备,1,，,5,双官能团化合物,2,Robinson,环化,A. 2-Methyl-2-(3-oxobutyl)-1,3-cyclopentanedione.,A 1.0-L, three-necked, round-bottomed flask equipped with a condenser, magnetic stirring bar, and thermometer is,charged with,112.1 g (1.0 mol) of 2-methyl-1,3-cyclopentanedione,230,mL,of,deionized,water,3.0,mL,of glacial acetic acid, and,140,mL,(120.96 g, 1.72 mol) of methyl vinyl,ketone,.,The system is shielded from light with aluminum foil and placed under a slight positive pressure of nitrogen. The flask is placed in an oil bath and the temperature is raised to 70C. The reaction is monitored by gas chromatography (GLC) until complete (12 hr).,The mixture is cooled, transferred to a,separatory,funnel, and extracted with 500,mL,and then two 100-ml portions of dichloromethane.,The combined extracts are washed with 500 and 100,mL,of saturated brine.,The combined brine wash is extracted with a further two 100-mL portions of dichloromethane.,The total dichloromethane extract is dried over sodium sulfate and filtered. The solvent is removed on a rotary evaporator at 45C (70 mm).,Drying on the rotary evaporator at 4045C (0.03 mm) for 16 hr gives 181.8 g (100%) of the desired,triketone,as an orange oil .,B. ( + )-(3aS,7aS)-2,3,3a,4,7,7a-Hexahydro-3a-hydroxy-7a-methyl-1 H-indene-1,5(6H)-dione.,A 500-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar and a nitrogen inlet is charged with,188,mL,of N,N-,dimethyl-formamide,and,863 mg (7.5,mmol,) of S-( )-,proline,. The mixture is degassed four times by alternate evacuation and refilling with nitrogen. The system is shielded from light with aluminum foil and the contents of the flask are stirred in a 1516C bath for 1.0 hr.,To the resultant suspension is added 45.5 g (0.25 mol) of the 2-methyl-2-(3-oxobutyl)-1,3-cyclopentanedione prepared in Step A. A total of 62.5,mL,of N,N-,dimethylformamide,is used to ensure complete transfer.,The degassing procedure is repeated four times and stirring at 1516C is continued for 40120 h as the mixture becomes yellow and then brown. The reaction is monitored for completeness by TLC . The solution of the desired,ketol,is used directly in Step C.,C. ( + )-(7aS)-7a-Methyl-2,3,7,7a-tetrahydro-1H-indene-1,5(6H)-dione.,A 100-mL, three-necked, round-bottomed flask equipped with a magnetic stirring bar, pressure-equalizing dropping funnel, and nitrogen inlet is charged with 50,mL,of N,N-,dimethylformamide,. The contents of the flask are cooled to 20C with a dry iceacetone bath and 2.70,mL,(4.97 g, 48.6,mmol,) of concentrated sulfuric acid is added over 510 min at a rate to maintain a temperature of 15 to 20C.,The flask containing the solution of the,( + )-(3aS,7aS)-2,3,3a,4,7,7a-hexahydro-3a-hydroxy-7a-methyl-1H-indene-1,5(6H)-dione in N,N-,dimethylformamide,is placed in an oil bath and heated to 95C. When the temperature reaches 7075C,an 18.8-mL aliquot of the,concd,sulfuric acid in N,N-,dimethylformamide,solution is added in one portion. The reaction mixture is heated to 95C for 3.0 hr.,After 1.0 hr, an additional 7.5-mL aliquot of the,concd,sulfuric acid in N,N-,dimethylformamide,solution is added in one portion. The reaction is monitored for completeness by GLC and cooled.,The solvent is removed on a rotary evaporator at 45C (0.30.5 mm) to give a brown oil. The material is taken up in 375,mL,of dichloromethane.,The solution is washed with two 190-mL portions of 2.0 N sulfuric acid solution that have been saturated with sodium chloride,two 190-mL portions of saturated sodium bicarbonate solution that have been saturated with sodium chloride, and,190,mL,of saturated brine.,Each aqueous wash is extracted, in turn, with the same two 190-mL portions of dichloromethane. The combined dichloromethane solutions are dried over sodium sulfate and filtered, and the solvent is removed on a rotary evaporator at 40C (70 mm),to give 38.839.6 g of oily, brown semisolid.,This material is taken up in 78,mL,of ethyl acetate and the solution is applied to a dry column of 78 g of silica gel .,The column is eluted with 600,mL,of ethyl acetate, and the total,eluate,is stripped of solvent on a rotary evaporator at 40C (70 mm) to give 37.238.8 g of tan crystalline solid.,The solid is subjected to bulb-to-bulb distillation 3 at 120135C (0.1 mm) to give 35.936.9 g of a slightly yellowish (cream white) solid, mp 5661C, ,D,25,+324329 (toluene, c 1.0).,This material is taken up in 74,mL,of ether at reflux. The solution is brought at reflux to the point of turbidity with 19,mL,of hexanes. The mixture is seeded, allowed to stand at ambient temperature for 2 hr, and then chilled in a 17C water bath for 30 min .,The solid is collected by filtration on medium porosity sintered glass, washed with two 12-mL portions of cold (3C) 1 : 1,v/v,ether : hexanes and dried at 20C (70 mm) to give 28.731.3 g (7076%) of white crystalline solid, mp 6466C, ,D,25,+347.5349 (toluene, c 1.0), purity by GLC 99.499.5% .,Hajos,的应用：,Hajos,获得了具有手性的,Hajos,酮,并完成了天然睾丸酮的全合成,紫杉醇的合成,维生素,D,3,的合成,Robinson,环化的实例,7-,甲氧基,-4a-,甲基,-4,4a,9,10-,四氢菲,7-,甲氧基,-4a-,甲基,-4,4a,9,10-,四氢菲的制备：,N,2,11.4g(0.01mol),6-,甲氧基,-1-,甲基,-2-,四氢萘酮,25mL,甲醇加到,4.70g (0.085mol) KOH,80mL,甲醇，,8mL,水,-20,o,C,4.34g(0.02mol),甲基乙烯基酮,(30min),rt,15h,回流,4h,冷却，加冰水、,2M,盐酸溶液中和，乙醚提取，,干燥、过滤，蒸去溶剂，残留物进行柱层析，,得黄色结晶。（,62%,）,3,烯醇硅醚的,Michael,加成反应,羰基的,Michael,加成反应，除了直接通过现场生成的烯醇或烯醇负离子进行外，也可通过烯醇硅醚或烯胺进行。,TiCl,4,促进的,Michael,反应可在很低的温度下进行，副反应少，收率高。,四、羟醛缩合反应,1,自身缩合,Soxhlet,索氏提取器使收率,5,70,2,交叉的醛或酮的缩合,苯甲醛与苯乙酮缩合的查尔酮（,Chalcone,）,查尔酮类化合物具有多种药理作用和生物活性,同时它也是一种新型的有机非线性光学材料。以它为母体的化合物存在于甘草、红花等多种天然植物体中，是植物体内合成黄酮的前体，其本身也有重要的药理作用。查尔酮具有抗蛲虫作用,，,抗过敏作用，表现了多种药理作用,，,类黄酮化合物中的查尔酮，具有化学预防和抗肿瘤活性,.,得到反式烯,在取代基较少的,a-,C,位置,OH,-,条件下,在取代基较多的,a-,C,位置,H,条件下,碱性条件下，,a,-H,的酸性占主导， 动力学控制,酸性条件下，烯醇的稳定性占主导，热力学控制。,甲醛与含活泼,a,-H,羰基化合物，在强碱作用下缩合：羟甲基化反应,制备季戊四醇：,涂料工业重要原料,3,胺甲基化反应（,Mannich,）,醛酮与甲醛和胺（仲、伯胺）缩合得到,Mannich,碱。通常加入少量的酸，保持一定的酸性。,历程：,应用较广，,醛酮，羧酸，酯，酚或其他含芳香体系（如杂环等）的活泼氢，制备氨基酮。,托品酮：,1903,年，,19,步合成出。总收率,0.75%,。,1917,年,Robinson,用,Mannich,反应合成出。收率,17%,。,丙酮二羧酸、丁二醛和甲胺仅一步就合成了,托品酮,(,颠茄酮,),。莨菪，颠茄,一步反应法：,tropinone,托品酮,1,氨甲基化总是发生在取代基较多的,a,-C,上，酸性条件，形成取代基较多的位置的烯醇较稳定。,2,可分解得到,a,b,-,不饱和羰基化合物，并增加了一个碳原子。,3,在医药和生物碱的合成中有着广泛的应用价值，因而越来越被合成化学家所重视。,草绿碱,芦苇中可以提取得到的生物碱。可以制备色氨酸。也可以制备,b,-,甲基吲哚。,Mannich,碱受热可发生消除反应得到烯，再经加氢得到增加一个碳的化合物。,甲基酮和环己酮在,Mannich,反应中常用。,利用,N,H,的,Mannich,反应：,使用绕丹宁制备生物活性衍生物。,五、羧酸衍生物,比较常见的,Claisen,酯缩合,1,Reformatsky,反应,有机锌化物：,有机镁化物可与酯反应。,b,羧酸酯,2,Darzen,反应,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。,由,b,-,紫罗兰酮与氯乙酸乙酯制备维生素,A,的中间体,布洛芬,(Ibuprofen),的合成,a,卤代腈、,a,卤代酮均可以发生,Darzen,反应，用相转移催化剂可以在水相中进行。,3,Perkin,反应,芳醛（不含,a,H,）,与酸酐在碱性（羧酸钾）条件下加热缩合，得到,a,b-,不饱和芳酸。芳基上有吸电子基时，反应易于发生，有给电子基时，反应难以发生。,肉桂酸的合成：,4,Knoevenagel,反应,含有活泼的,CH,2,（,丙二酸酯、丙二酸、乙酰乙酸乙酯，氰乙酸乙酯）可以与醛酮在氨或仲、伯胺、六氢吡啶条件下，与不含,a,H,的醛反应缩合得到,a,b,-,不饱和酸。制备香豆素衍生物。,5,安息香缩合,多为芳醛，较少脂肪醛在,KCN,作用下得到,a-,羟基酮,安息香的制备,机理,不对称的,a,羟基酮,