合成化学Chapter4.ppt

1、Chapter 4 Oxidation Reactions,1,氧化反应,广义的概念 氧化失去电子的过程。 有机化合物碳原子周围电子云密度的降低，即碳原子氧化数（氧化态、氧化值）升高的反应。 狭义的概念 加氧反应和/或脱氢反应。,2,Oxidation State （氧化态）,3,氧化反应的分类,1. 碳原子上的氢被吸电子的基团或原子取代,2. 碳碳相联接转变成与吸电子基团或原子相联接,4,3. 脱氢,4. 官能团的氧化,5,4-1 烷基的氧化,6, 铬酐-醋酐（CrO3-Ac2O)氧化,1. 苄位氧化成醛,7,制备方法：a. HCl、H2SO4滴加到CrO3中，蒸馏除水 b. K2Cr2O7

2、与浓HCl或浓H2SO4+NaCl作用得到,铬酰氯（ CrO2Cl2, Chromyl chloride，tard埃塔试剂） 暗红色有刺鼻气味的液体，遇水剧烈分解，在空气中发烟,8,direct oxidation of an aromatic or heterocyclic bound methyl group to an aldehyde,9,Examples,(立体效应使邻位收率低),10,硝酸铈铵（Ce(NH4)2(NO2)6） Ceric Ammonium Nitrate (CAN),（反应在酸性介质中进行，不论有几个甲基，最终只氧化一个）,11,铬酸：,2. 苄位氧化成酮或酸,Ex

3、ample,12,Examples,13,KMnO4为氧化剂,不管侧链多长均被氧化成 -COOH,14,硝酸为氧化剂（稀硝酸）,只氧化一个-CH3,15,空气氧化（O2) （在碱或钴盐存在下，空气氧化可使苄位甲基氧化成羧基）,Examples,16,Pb(OAc)4 (LTA) Hg(OAc)2,3. 羰基a-位的氧化,17,SeO2为氧化剂,18,Examples,19, SeO2/H2O/HOAc,4. 烯丙位的氧化,a. 当有多个烯丙位时，优先氧化取代基多的一侧的烯丙位,20,b. 在a原则下，CH2CH3 CHR2,c. 在ab相矛盾时，遵循a原则,d. 环内双键，在b前提下优先氧化环

4、上的烯丙位,21, 有机过酸酯 （引入酰氧基后水解）,烯丙醇,22,铬酐吡啶（分子内盐） （CrO3.2Py, Pyridinium dichromate, PDC）,23,4-2 烯烃的氧化,1. KMnO4 氧化,a. 烯烃被冷的碱性KMnO4氧化生成顺式邻二醇,24,b. 烯烃被酸性或碱性加热的KMnO4氧化，会发生烯烃的氧化断裂，生成酮、酸或酮酸混合物。,25,2. 臭氧化(Ozonolysis) ozone (O3),26, Dimethyl sulfide is the most commonly used reducing agent. Others include I2, ph

5、osphine, thiourea, catalytic hydrogenation, tetracyanoethylene, ZnHOAc, LiAlH4, and NaBH4. The latter two reductants afford alcohols as products. Oxidative workup provides either ketone or carboxylic acid products. The most common oxidants are H2O2, Ag2O, CrO3, KMnO4, or O2. Alkenes with electron-do

6、nating substituents are cleaved more readily than those with electron-withdrawing substituents.,27,Reductive workup mechanism,Oxidative workup mechanism,28,Examples,29,Oxidation of alkynes,30,3. Epoxidation,Comprehensive Org. Syn., Vol. 1, 819; Vol. 7, 357, 390.,3.1 Peracid Oxidation,31,1） Peracid R

7、eactivity,The lower the pKa, the greater the reactivity (i.e., the better the leaving group),The reactivity order of Bayer-Villiger oxidants parallels the acidity of the corresponding carboxylic acid (or alcohol): CF3CO3H p-nitroperbenzoic acid HCO3H m-CPBA PhCO3H CH3CO3H HOOH t-BuOOH.,32,2) Mechani

8、sm,过氧酸对双键发生亲电进攻，形成环氧化合物。,Org. Lett., 2003, 5, 3787-3790.,33,3) Chemoselectivity,-Electrophilic reagent: most nucleophilic C=C reacts fastest.,34,Examples:,35,4) Stereochemistry,Stereochemistry of olefin is maintained: diastereospecific. Reaction rate is insensitive to solvent polarity concerted mech

9、anism without intermediacy of ionic intermediates. c. Less hindered face of olefin is epoxidized.,36,5) Diastereoselectivity, Endocyclic Olefins,37, Allylic Alcohols (endocyclic),Henbest, J. Chem. Soc., 1957, 1958; Proc. Chem. Soc, 1963, 159.,38,H-bonding to proximal peroxide oxygen directs epoxidat

10、ion to the same face as OH group and accelerates/facilitates the reaction.,39, Other Directed Epoxidations,Studies suggest axial NHCbz delivers syn epoxide while equatorial does not.,40,6) Scope and Limitations,a. Olefin geometry is maintained.,b. Reaction is diastereospecific: the stereochemistry o

11、f the reactant and product bear a definite relationship to one another.,c. Reaction can be buffered to prevent epoxide opening.,41,d. Common Side Reactions:, Baeyer-Villiger Reactions of Ketones (and aldehydes),42, Oxidation of amines,-Nitrogen must be protected (e.g. as amide) or another reagent se

12、lected., Imine oxidation, Sulfur oxidation,43,7) Epoxidation of Electron-Deficient Olefins, -unsaturated esters: can choose a strong peracid or vigorous reaction conditions.,Emmons, J. Am.Chem.Soc., 1955, 77, 89.,MacPeek, J. Am. Chem. Soc. 1959, 81, 680.,b. , -unsaturated ketone: Baeyer-Villiger com

13、petes with epoxidation,Solution: different conditions (reagents) are needed.,44,3.2 H2O2 Oxidation,H2O2 + NaOH,45,-The following reaction is diastereoselective (not diastereospecific),The reaction occurs via a reversible process:,tBuOOH/Triton B Payne, J. Org. Chem., 1961, 26, 651. Ph3COOH/R4NOH Cor

14、ey, J. Am. Chem. Soc. 1988, 110, 649. tBuOOH/nBuLi Cegg, Tetrahedron, 1988, 29, 48889.,Similarly:,46,Urea-H2O2,a safe alternative to H2O2,47,3.3 Dimethyl Dioxirane (DMDO),Murray J.Am. Chem Soc, 1986,108,2470. Acc.Chem. Res., 1989, 22,205,A mild neutral reagent,制备,48,Examples,49,Examples,50,51,3.4 Su

15、mmary of Other Methods of Epoxide Formation,a. Cyclization of Halohydrins,52,b. Cyclization of 1,2-diols,c. Epoxides from Carbonyl compounds,Asymmetric variants / Evans Chiral Oxazolidinone,Lantos, J. Am. Chem. Soc., 1986, 108, 4595.,53,3.5 Catalytic Asymmetric Epoxidation,1）Sharpless Catalytic Asym

16、metric Epoxidation (AE Reaction),Key reference: Asymmetric Synthesis: Vol. 5, Morrison J. D. Ed. Chapter 7 and 8,Reviews: Katsuki, Martin Org. React., 1996, 48, 1. Comprehensive Org. Syn., Vol. 7, 389436.,Sharpless J. Am. Chem. Soc., 1980, 102, 5974; 1981, 103, 6237; 1984, 106, 6430; 1987, 109, 1279

17、, 5765; 1991, 113, 106, 113; 1987,109,1279,2001 Nobel Prize in Chemistry K. Barry Sharpless, William S. Knowles and Ryji Noyori,54,(1) The enantiofacial selectivity of the reaction is general and dependable for assignments.,55,(2) Selectivity is catalyst dependent:,Ti(OiPr)4 95% e.e. Zr(OiPr)4 10% e

18、.e. Al(OtBu)3 5% e.e. Hf(OiPr)4 3% e.e. MoO2(acac)2 15% e.e. Nb(OEt)3 5% e.e. VO(OiPr)3 17% e.e. Ta(OiPr)5 39% e.e. Sn(OiPr)4 NR,56,(3) Sharpless Asymmetric Epoxidiation,-Match of Ti/Tartrate such that a single complex dominates the chemistry.,-Ligand acceleration of reaction.,-Steric and stereoelec

19、tronic feactures of reaction control enantioselectivity.,the best known and practical asymmetric reaction,57,Examples,酒霉素,红霉素,白三烯C-1,(+)-环氧十九烷,58,(4) Kinetic Resolution,Sharpless, J. Am.Chem.Soc.,1981, 103, 6237 Pure Appl. Chem., 1983, 55, 589.,- Sharpless epoxidation product is different from the d

20、irected oxidation of allylic alcohols by peracids (m-CPBA),59,60,2） Jacobsen Epoxidation,Unactivated alkenes + chiral salen-Mn complex,61,Jacobsen, J. Am.Chem.Soc., 1991, 113, 7063. Synlett 2003, 281.,Examples,62,4. Dihydroxylation,First use: Criegee Justus, Liebigs Ann. Chem. 1936, 522, 75. Milas,

21、J. Am. Chem. Soc. 1936, 58, 1302.,63,4.1 Olefin Osmylation,Mechanism,64,Characters,OsO4 is an electrophilic reagent, and it behaves as a large reagent. Strained, unhindered olefins react faster than unstrained, sterically hindered olefins. Electron-rich olefins react faster than electron-deficient o

22、lefins. Diastereospecific, with attack on the C=C from the least hindered face.,-Alternative reagent to OsO4:,- but OsO4 is expensive, volatile, and toxic,- various improvements:,KMnO4: Synthesis 1987, 85. Yields rarely as high as OsO4 but less hazardous and less expensive especially for large scale

23、,65,Diastereoselectivity,a. Endocyclic Olefins,66,67,b. Acyclic Systems,68,- Also observed with allylic ethers,69,TMEDA effect,70,Diol Stereochemistry Comparision,m-CPBA,OsO4,71,Via Bromohydrin,Epoxidation on most hindered face of olefin to give different epoxide from m-CPBA, trans diaxial ring open

24、ing to give same hydrolysis product as from m-CPBA oxidation,72,4.2 Asymmetric Dihydroxylation reaction catalyzed by OsO4-related reagents,1. Catalytic Methods,反应条件温和，无需低温、无水、无氧等条件。,73,Sharpless asymmetric dihydroxylation,74,75,Mechanism,Good or excellent selectivity,Poor selectivity,Corey J. Am.Che

25、m. Soc., 1987, 109, 6213.,76,Summary of oxidation of an alkene,77,Chromium-based Oxidation Reagents,Collins reagents: CrO3-Py2, alkaline oxidant,Jones Reagents: CrO3 in aq. H2SO4/acetone,Pyridinium Chlorochromate (PCC),Pyridinium Dichromate (PDC):,4-3 醇的氧化 Oxidation of Alcohols,78,Manganese-based Ox

26、idation reagents,MnO2 (Activated),KMnO4 / H2SO4,KMnO4 / t-BuOH-5% NaH2PO4 aq. buffer,R4NMNO4,Cu(MnO4)2-6H2O and Ba(MnO4)2,79,Other Oxidation Reagents,NaOCl / NaClO2,Ag2O / Ag2CO3,m-CPBA / NaIO4,Dess-Martin Reagent,Nitroxide,Openauer Oxidation: Al(OiPr)3+ketone,DMSO,80,1）铬酸 H2CrO4 CrO3溶于水或重铬酸盐溶于酸性水溶液

27、,1. Cr氧化剂,81,Mechanism,82,Examples,83,Jones试剂: CrO3+diluted H2SO4+丙酮,2）Jones试剂,特点：氧化速度快，严重放热，产率高，不氧化C=C。,84,（不氧化苄甲基）,氧化不饱和醇，双键不受影响,Examples,85,Examples,J. Am. Chem. Soc. 1978, 100, 4618-4620.,Angew. Chem., Int. Ed. 1999, 38, 3175-3177.,86,3）铬酐吡啶络合物 Collins reagent: CrO32Py diluted in CH2Cl2 PCC/ Sar

28、ett试剂: C5H5NH+CrO3Cl-, 氯铬酸吡啶盐 PDC: (C5H5NH)2Cr2O7, 重铬酸吡啶盐,适合于所有对酸敏感的官能团的醇类氧化,PDC,87,Examples,J. Am. Chem. Soc. 1980, 102, 2117-2120.,88,Tetrahedron Lett. 1990, 31, 2109-2112.,89,J. Org. Chem. 1995, 60, 2200-2204.,Tetrahedron 1988, 44, 2149-2165.,J. Org. Chem. 1986, 51, 230-238.,Examples,90,1）KMnO4 冷

29、、稀、中性KMnO4不能氧化醇，在强烈的条件下（如酸、碱、加热）才能氧化醇。 KMnO4活性： 酸性碱性中性 (加热有利于反应),2. Mn氧化剂,91,J. Am. Chem. Soc. 1992, 114, 10181-10189.,92,2) 活性MnO2 新鲜制备的MnO2，用于烯丙醇的氧化,93,二甲亚砜可被DCC、Ac2O、三氟乙酸酐、草酰氯、 三氧化硫等活化，在温和条件下将醇氧化。,3. 二甲亚砜(DMSO),94,1）Pfitzner-Moffatt Oxidation DMSO+DCC,95,Org. Synth. Coll. Vol. VI 1988, 220-222.,C

30、an. J. Chem. 1981, 59, 870-877.,Examples,96,2）DMSO-Ac2O(能氧化选择性差、位阻大的醇),97,3）Swern oxidation: DMSO-(COCl)2-Et3N,伯醇、仲醇制备醛酮,98,反应条件温和，对于底物的官能团耐受性好，适用范围广泛。,Mechanism,99,J. Org. Chem., 2007, 72, 7052-7057.,Examples,J. Org. Chem. 2000, 65, 3738-3753.,100,4）Parikh-Doering oxidation (DMSO+SO3Py+Et3N),反应一般在室

31、温或0C下进行，可以只产生少量的甲硫甲基醚副产物。,101,J. Am. Chem. Soc. 2009, 131, 1058710597.,Angew. Chem. Int. Ed. 1999, 38, 3175-3177.,Examples,102,4. Oppenauer oxidation (Al(i-PrO3 + excess acetone),特点：催化剂相对便宜，毒性低，条件温和，不适合伯醇的氧化，对仲醇的 氧化有高选择性，产物为对应的酮，在甾族化合物、荷尔蒙、生物碱和萜烯 类化合物的合成中应用广泛。,103,Mechanism,104,反应可逆，加大丙酮量（既作溶剂又作氧化剂）

32、,黄体酮,Examples,105,5. TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl,106,把醇氧化成醛酮；酸性条件，伯醇仲醇氧化速度差不多，碱性条件下位阻小的氧化快，一般与其他氧化剂共同使用。,Tetrahedron Lett., 1992, 33, 5029.,J. Org. Chem., 1996, 61, 7452.,Examples,107,6. Ley Oxidation (TPAP+NMO) TPAP: Tetrapropylammonium perruthenate, Pr4N+RuO4- NMO:N-methylmorphol

33、ine N-oxide,108,Molecules, 2000, 5, 82-88 .,J. Chem. Soc., Perkin Trans. 1, 1997, 3291.,Examples,109,反应有水产生，一般需要加分子筛；也可以把仲醇氧化为酮。,1) DessMartin periodinane,制备,7. 碘化物氧化,110,o,o,Mechanism,特点：官能团耐受性好，不会氧化双键，反应条件温和，反应速度快，不怕水， 有少量水存在还可以加快反应进程。,111,J. Am. Chem. Soc. 1988, 110, 6890-6891.,Org. Lett., 2011, 13, 1036-1039.,Examples,112,Tetrahedron Lett. 1994, 35, 8019-8022.,Examples,J. Am. Chem. Soc. 2000, 122, 7596-7597.,113,2) HIO4 邻