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1、1. Michael 加成,Michael 加成烯醇负离子与a, b-不饱和羰基化合物的共轭加成,Michael acceptor,Michael donor,注意产物的结构,机理,Michael加成,1, 5-二羰基化合物,五 经典 碳负离子反应,醛、酮 + a, b-不饱和酮,六员环状烯酮,2. Robinson Annelation (Robinson 关环),作业1,作业7,作业3,南开,分析：,写出下列转变的机理：,大连理工,分析：,Pka=11,b-羰基酸酯,3 The claisen condensation: -keto esters,The claisen condensat
2、ion: -keto esters,Notice that one molecule of the ester(deprotonated, reacting as the enolate) serves as the nucleophile to attack another molecule of the ester, which serves as the acylating reagent in this nucleophilic acyl substitution.,the intermediate has an alkoxy (-OR) group that acts as a le
3、aving group,leaving a - keto ester. The overall reaction combines two ester molecules to give a - keto ester.,4 Dieckmann condensation,An internal Claisen condensation of a diester forms a ring. Such an internal claisen cyclization is called a Dieckmann condensation. Five- and six- membered rings ar
4、e easily formed. Rings larger than six carbons or smaller than five carbons are rared formed by this method.,南开,分析前者按照酮酯缩合机理形成 后者是酮发生烯醇互变，烯醇与酯发生酯交换生成,由环己烯和其他小于等于3个碳的化合物合成,并写出该反应的可能机理。,写出该反应的可能机理,Wittig反应举例,(1),(2),反应有选择性, 酯基不受影响,三苯基亚甲鏻,ylide,(3),反应条件温和，不发生重排，产率较高，在特定位置形成碳碳双键。,反应有选择性, 酯基不受影响,德国海得堡大学
5、Wittig教授 1979 诺贝尔化学奖,5. Classic Alkylation Methods,Acetoacetic ester synthesis ： Alkylation or acylation of acetoacetic ester (ethyl acetoacetate),Followed by hydrolysis and decarboxylation,to give substituted acetone derivatives.,酮式分解,酸式分解,性质,应用 1：制备取代丙酮类化合物,单取代丙酮,二取代丙酮,乙酰乙酸乙酯在合成上的应用,Ethyl acetoace
6、tate has acidic alpha-hydrogens. When reacted with sodium metal, the ester is converted into its conjugate base (an enolate anion). The enolate can be used as the nucleophile in an SN2 reaction with a 1o or CH3 alkyl halide. Upon hydrolysis, the substituted acetoacetic acid will decarboxylate when h
7、eated. Product is a ketone derived from acetone.,浙江大学,制备环烷基甲基酮,乙酰乙酸乙酯 : 二卤代烃1 : 1,复旦,1, 3-二羰基,1, 5-二羰基,用丙二酸酯法合成,添加酯基,合成路线 a,三乙,酮的酰基化机理,酮与酯的a - 氢酸性比较：,优先?,Reformatsky反应,EtOH,合成路线 2（用Reformatsky反应制备a, b-不饱和酯）,Reformatsky 试剂,练：,例：,小结,合成等价物,作用： 活化反应：使反应易进行，产率高。 定位作用：使反应有较好的区位选择性。,关键：引入酯基,Aldol缩合,Claisen
8、 缩合Dieckmann缩合 酮的酰基化,Michael加成,a位烷基化,一些羰基化合物a位的缩合反应归纳,b-二酮,b-羰基酯,1, 3-二羰基型化合物的反合成分析,酯 酮,酯酯,酮酯,Michael加成,1, 5-二羰基,1, 4-二羰基,羰基化合物 a卤代羰基化 合物,(1) Michael加成 (2) Dieckmann缩合 或 分子内酮酯缩合,Robinson关环 (1) Michael加成 (2) Aldol缩合,6元环状1, 3-二羰基,6元环状烯酮,酯碳负离子,酸性条件,1, 5-二羰基,(1),醇醛缩合,Michael 加成,醇醛缩合,Robinson关环,请完成正向合成,0
9、3中科院,制备甲基二酮类化合物,乙酰乙酸乙酯 : 二卤代烃2 : 1,1.3二羰基(氧) 化合物 酯缩合三乙 1.4二羰基(氧)化合物 羰基负离子+卤代物 1.5二羰基(氧)化合物 羰基负离子+不饱和物 不饱和化合物 羟醛缩合,1,5二羰基化合物：麦克加成, 含活泼氢的羰化物,需添酯基，保证活泼氢酸性足够大,作业1,08南开,作业2,作业3,06中科院,作业4,Malonate synthesis of carboxylic acids. Diethyl malonate has acidic alpha-hydrogens When reacted with sodium metal, th
10、e ester is converted into its conjugate base (an enolate anion),The Malonic Ester Synthesis of Substituted Acetic Acids,By a similar sequence of alkylation, hydrolysis, and decarboxylation, substituted acetic acids may be prepared from diethyl malonate. Malonic ester synthesis,The enolate can be use
11、d as the nucleophile in an SN2 reaction with a 1o or CH3 alkyl halide. Upon hydrolysis, the substituted malonic acid will decarboxylate when heated. 5. Product is a carboxylic acid derived from acetic acid.,(1) 制法,四 丙二酸二乙酯,(2) 性质,应用1： 制备取代乙酸,二取代乙酸,(3) 丙二酸二乙酯在合成上的应用,一取代乙酸,中科大,Malonate Two-Stage Alkyl
12、ation Example,Decarboxylation of the malonic acid proceeds via a cyclic transition state that initially produces the enol of the carboxyl acid.,Malonate Alkylation Using Dihaloalkanes,There are two varieties of outcome, depending on the ratio of malonate to dihaloalkane. EXAMPLES:,Retrosynthetic Ana
13、lysis and Malonic Ester Synthesis,If the target molecule is a carboxylic acid, consider it as a “substituted acetic acid” and then identify the alkyl groups that need to be introduced.,应用4：麦克加成,（2）Wieland-Miesher 酮反合成分析,Wieland-Miesher 酮的合成路线,(i) 中间体 的合成（方法 a ）,(ii) 第二个环的形成Robinson关环,方法 b 的合成路线请自己完成
14、,1o 醇,2o 醇（R = H）,3o 醇,3o 醇,1o 醇（R = H）,2o 醇,六、格式试剂相关合成,1,科大,科大98,97科大,丙二酸二乙酯 : 二卤代烃1 : 1,制备环烷基乙酸,中科大,丙二酸二乙酯 : 二卤代烃2 : 1,应用2：制备二元羧酸,复旦,Michael Additions of 1,3-Dicarbonyls,The addition of 1,3-dicarbonyls to,-unsaturated carbonyl compounds under base-catalyzed conditions are referred to as Michael ad
15、ditions. These additions are understandable in terms of concepts already discussed that describe the formation and reactivity of enolate anions derived from 1,3-dicarbonyl compounds and the mode of addition to conjugated enone systems.,A Mechanism,Further Synthetic Modifications,Alkaline hydrolysis
16、and heating to induce decarboxylation of the malonic acid subunit yields 3,3-dimethylglutaric acid.,The Mannich Reaction,In this reaction, and-hydrogen is replaced with an aminomethyl group.,应用3：制备环烷基二元取代乙酸,复旦,应用4 ：麦克加成,07中科院,PCC氧化剂也称为沙瑞特（Sarrett）试剂， Pyridinium chlorochromate 全名：Pyridinium chlorochromate PCC是吡啶和CrO3在盐酸溶液中的络合盐，是橙红色晶体。它溶于CH2Cl2，使用很方便，在室温下便可将伯醇氧化为醛，而且基本上不发生
