1、Chapter 2 Formation of Carbon-Carbon Single Bonds,一、General Principles,烷化反应： E = 烷化剂 缩合反应： E = 醛、酮、酯等 Michael 加成：E =,Mannich 反应,二、影响反应的主要因素,a. 反应底物 （Substrate),-NO2 -COR SO2R -CN -CO2R -Ph , SOR,A和B至少要有一个是 EWG,A和B应该能使其 -碳上的H活化的基团，通常为吸电子基（Electron withdraw group EWG）。,b. 碱 （Base）,常用的碱： Ph3C- (Me2CH)2
2、N- EtO- OH- R3N碱的选择取决于底物的反应活性,理想的碱：碱性强，亲核性弱，并不进攻那些较敏感的基团，另外能溶于非极性溶剂中。,c. 溶剂 （Solvent),Solvent,O- alkylation C-alkylation,反应速度,常用的非质子极性溶剂 （polar aprotic solvent):,DMF DMSO HMPA,d. 亲电试剂 （Electrophilic reagent),所有能与负碳离子发生反应的碳正离子或分子。,例： RX, R-SO3H, RCO2Et, RCOR,这四种影响因素之间是相互联系，相互影响的。在分析 一个具体反应时，应该综合分析考虑这
3、四种影响因素。,三、烷基化反应 (Alkylation),1. O-alkylation & C-alkylation,Example 1,Example 2,Degree of substitution of alkylating agent:,Example 3,2. 区域选择性 （Regioselectivity),区域选择性受热力学控制和动力学控制的反应条件影响很大.,热力学控制条件下主要生成取代基较多的烯醇; 动力学控制条件下主要生成取代基较少的烯醇;,Example 1,Example 2,3. 立体选择性 （Steroselectivity),烯醇化合物的立体选择性形成, 将为不
4、对 称合成提供平台.,Example 1,Example 2,Example 3,Example 4,4. 二羰基化合物的 -烷基化反应 ( -Alkylation of 1, 3- dicarbonyl compounds),J. Am. Chem. Soc., 1974, 90, 1082; 1963, 85, 3237; 1965, 87, 82.,Example 1,Example 2,Example 3,继承与发展,5. 芳基卤化物与烯醇盐的反应 (Reactions of aromatic halide with enolates),Example,Mechanism,关键是要有形
5、成苯炔的条件。,6. 酮和酯的烷基化反应 (Alkylations of ketones and esters),避免Aldol 缩合反应发生的方法： 烷化剂要待酮完全转化为烯醇式后再加入。,常用的碱：NaNH2, KNH2, NaH, Ph3CNa 等；有副产物。LDA, LTMP, LHMDS 等效果很好。,Example 1,Example 2,不对称酮的选择性烷基化反应 (Selective alkylation of asymmetric ketones),在一个 - 位引入一个活化基 (略）如： Dieckmann Reaction; Claisen condensation,制成
6、结构专属性的烯醇负离子,在取代基较多的 - 位烷基化 (烯醇硅醚法),碱性条件,酸性条件,在取代基较少的 - 位烷基化 (烯胺法, Stork Enamine Synthesis),通常，用活泼的卤代烷，可以高产率生成C-烷基化产物；但对于一般的卤代烃， C-烷基化产物收率较底。若用LDA在低温下反应，则对各种卤代烃均可得到高收率的C-烷基化产物。对于不对称酮，主要在取代基较少的 - 位发生烷基化。,Example 1,Example 2,7. 对映选择性烷基化反应（Enantioselective alkylations),利用手性胺,利用二甲基肼,扩展： 二甲基腙锂化合物的另一应用,二甲基
7、腙锂化合物容易转化成有机铜化合物，而有机铜化合物在C-C键的形成中很有用。,利用SAMP 和 RAMP,若用 RAMP， 则得到另一 种对映异构 体。,羧酸的-不对称烷基化,Example,8. 极性翻转（Umpolung),俞凌翀，刘志昌，极性转换及其在有机合成中的应 用，科学出版社，1991,Example 1 安息香缩合,Example 2 醛氰醇法,Example 3 1, 3 二噻烷法,不易发生Michael 加成反应。,Example 4 乙基乙硫甲基亚砜法,1, 4 二酮,四、缩合反应 (Condensation),Aldol Reaction Michael Addition
8、Mannich Reaction Claisen Condensation Dieckmann Condrnsation Darzens Reaction Reformatsly reaction,Aldol Reaction (condensation),1) 经典Aldol 反应的两大缺点,不同醛、酮之间的反应常得到混合产物；立体选择性差,2) 定向醇醛缩合反应 （Directed Aldol condensation),Metood 1 Preformed Lithium Enolates,Z-enolates give predominantly syn (or threo) aldo
9、l products (thermodynamic enolates).E-enolates give predominantly anti (or erythro) aldol products (kinetic enolates).,Example 1,- Steric size of R1 affects diastereoselectivity,Origin of Diastereoselectivity,a. Z-enolates,Diastereoselectivity for Z-enolate (giving syn aldol product) is maximized wh
10、en R1 and R3 are sterically demanding (R1/R3 interaction is maximized).Diastereoselectivity also increases as metal is changed to boron. This is attritubted to a tighter T.S. (BO bond shorter, so R1/R3 steric interactions are magnified in T.S. for anti product).When R2 is very large the R3/R2 gauche
11、 interaction R1/R3 1,3-diaxial interaction (Why?).,b. E-enolates,Diastereoselectivity increases as R1 and R3 become sterically large, and a switch to the boron enolate will increase selectivity.Diastereoselectivity may switch when R2 is very large (Why?).,Effect of R1,Effect of R3,Effect of R2,Metoo
12、d 2 Preformed Boron Enolates,a. Z-enolate Preparation and Reactions,b. E-enolate Preparation and Reactions,- Originally difficult to control but:,c. Examples of more recent methods to control boron enolate geometry,Aldol Condensation with Chiral Enolates,Ti enolate promoted Evans aldol (non-Evans sy
13、n aldol),Chelated and non-chelated Ti enolates,Metood 3 Acid-Catalysed Directed Aldol Reactions,该方法是 在酸性条件 下反应；但 立体选择性 较差。,3) 有机小分子催化醇醛缩合反应,（Small Organic Molecules Catalysted Aldol Reactions),Novel Small Organic Molecules for a Highly Enantioselective Direct Aldol Reaction,J. AM. CHEM. SOC. 2003, 1
14、25, 5262-5263,Zhuo Tang, Fan Jiang, Luo-Ting Yu, Xin Cui, Liu-Zhu Gong,*, Ai-Qiao Mi,Yao-Zhong Jiang, and Yun-Dong Wu*,Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, College
15、 of Chemical Engineering, Sichuan UniVersity, Chengdu, 610065, China, and State Key Laboratory of Molecular Dynamics and Stable Structures, College of Chemistry and Molecular Engineering, Peking UniVersity, Beijing, 100871, China,2. Michael Addition Reaction,Applications: Synthesis of 1,5-dicarbonyl
16、 compounds,General Scheme,Development: Asymmetry Michael Addition Reaction,手性金属配位化合物催化,Macmillan Groups Work,Small Organic Molecule catalyzed asymmetric Michael reactions,The First Enantioselective Organocatalytic Mukaiyama-Michael Reaction:,S. P. Brown, N. C. Goodwin, and D. W. C. MacMillan*, J. Am
17、. Chem. Soc. 2003, 125(5), 1192-1194,3. Mannich Reaction,General Scheme, 胺组份 氨、伯胺、仲胺, 醛组份 HCHO, PhCHO, RCHO,可分别发生三、双、单 Mannich 反应, 活泼 H 组份,醛、 酮、 活泼亚甲基化合物、酚类化合物、杂环、炔等。,Example 2,Example 1,Development: Asymmetry Mannich Reaction,Lewis acid-catalyzed asymmetric Mannich reactions,(a) Fujii, A.; Hagiwara
18、, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450; (b) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 8180; (c) Ishihara, K.; Miyata, M.; Hattori, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520; (d) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997, 119, 2060; (
19、e) Ferraris, D.; Yong, B.; Dudding, T.; Leckta, T. J. Am. Chem. Soc. 1998, 120, 4548; (f) Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67. (g) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem. Soc. 2002, 124, 56
20、40.,(a) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III Tetrahedron Lett. 2001, 42, 199; (b) Juhl, K.; Gathergood, N.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995; (c) Yamasaki, S.; Iida, T.; Shibasaki, M. Tetrahedron 1999, 55, 8857; (d) List, B. J. Am. Chem. Soc. 2000, 12
21、2, 9336; (e) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1842; (f) Cordova, A.; Watanabe, S.-i.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124, 1866.,Small Organic Molecule catalyzed asymmetric Mannich reactions,The Direc
22、t and Enantioselective, One-Pot, Three-Component, Cross-Mannich Reaction of Aldehydes,Angew. Chem. Int. Ed. 2003, 42, 3677 3680,Y. Hayashi,W. Tsuboi, I. Ashimine, T. Urushima,Dr. M. Shoji Department of Industrial Chemistry, Faculty of Engineering Tokyo University of Science, Kagurazaka,Three-compone
23、nt Mannich reaction with various acceptor aldehydes,N-methyl-2-pyrrolidinone (NMP),Three-component Mannich reaction with various donor aldehydes.,4. Claisen Condensation,General Scheme,Mechanism, 一种酯的自身缩合,Scope of application, 一种含 -H 的酯与一种不含 -H的酯之间的缩合,Examples,Directed Claisen condensation,5. Dickmann Condensation,
